Process for preparing the antiviral agent [1S-(1alpha, 3alpha, 4beta)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one

ABSTRACT

Processes are disclosed for preparing the antiviral agent entecavir. A resin adsorption process for the isolation and purification of entecavir is also disclosed. Various intermediates useful in the preparation of entecavir are also disclosed.

RELATED APPLICATIONS

This application claims the priority benefit of U.S. ProvisionalApplication No. 60/432,549 filed Dec. 11, 2002, the disclosure of whichis incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Entecavir,[1S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one,is currently being evaluated as a drug for use in treating hepatitis Bviral infections.

Entecavir and its use as an antiviral agent are described in U.S. Pat.No. 5,206,244 to Zahler et al., assigned to the present assignee.Improved processes of preparing entecavir are described by Bisacchi etal., in WO 98/09964, also to the present assignee.

Colonno, et al. in WO 01/64221 describe compositions containing a lowdose of entecavir administered on a daily basis to treat hepatitis Bvirus infection and/or co-infections.

SUMMARY OF THE INVENTION

This invention is directed to various methods for preparing entecavir asrecited in the claims appended hereto. Entecavir (the compound offormula 21) has the structural formula shown below:

This invention is also directed to various intermediates useful in thepreparation of entecavir and the methods of preparing suchintermediates.

This invention is also directed to a resin adsorption process forisolation and purification of entecavir and intermediates thereof.

DETAILED DESCRIPTION OF THE INVENTION ABBREVIATIONS

For ease of reference, the following abbreviations are used in thisapplication and have the meanings given below:

-   Ac=acyl;-   AP=HPLC area percent;-   Bn=benzyl;-   BHT=2,6-di-tert-butyl-4-methylphenol;-   CHP=cumene hydroperoxide, or α,α-dimethylbenzylhydroperoxide;-   DCM=dichloromethane;-   de=diastereometric excess;-   DBU=1,8-diazabicyclo[5.4.0]undec-7-ene;-   DEAD=diethylazodicarboxylate;-   DEMA=diethoxymethyl acetate;-   DIPT=(−)-diisopropyl tartrate;-   DMAP=4-N,N-dimethylaminopyridine;-   DMF=N,N-dimethylformamide;-   DiPMA=di-isopropyloxymethyl acetate; [(iPr—O)₂CHOAc];-   DMSO=dimethyl sulfoxide;-   ee=enantiomeric excess;-   Et=ethyl;-   EtOAc=ethyl acetate;-   Et₃N=triethylamine;-   FMSA=fluoromethane sulfonic acid;-   HCl=hydrochloric acid-   IPA=isopropanol;-   K₂CO₃=potassium carbonate;-   KF=potassium fluoride;-   KHCO₃=potassium bicarbonate;-   KHMDS=potassium hexamethyldisilazide or_potassium    bis(trimethylsilyl)amide;-   KOH=potassium hydroxide;-   KOtBu=potassium tert-butoxide;-   LAH=lithium aluminum hydride;-   LiOH=lithium hydroxide;-   m-CPBA=meta-chloroperbenzoic acid;-   MeOH=methanol-   MOP=2-methoxy-2-propoxy-acetal;-   MSA=methanesulfonic acid;-   MTBE=methyl tert-butyl ether;-   NaBH₄=sodium borohydride;-   Na₂CO₃=sodium carbonate;-   NaHCO₃=sodium bicarbonate;-   NaH=sodium hydride;-   NaOH=sodium hydroxide;-   NaOtBu=sodium tert-butoxide;-   NMP=N-methyl-2-pyrrolidinone;-   TMS=trimethylsilyl;-   PPTS=pyridinium 4-toluenesulfonate or pyridiniump-toluenesulfonate;-   PTSA=para-toluene sulfonic acid;-   Red-Al® or RED-AL®=sodium bis(2-methoxyethoxy)aluminum hydride;-   TBAH=n-tetrabutyl ammonium hydroxide;-   TBHP=tert-butylhydroperoxide;-   TEOF=tri-ethylorthoformate;-   TFA=trifluoroacetic acid;-   THF=tetrahydrofuran; Ti(O-iPr)₄=titanium (IV) isopropoxide;-   TiPOF=trisopropylorthoformate;-   TMOF=trimethylorthoformate.

DEFINITIONS

The following terms shall have, for the purposes of this application,including the claims appended hereto, the respective meanings set forthbelow. It should be understood that when reference herein is made to ageneral term, such as acid, base, oxidizing agent, etc. one skilled inthe field may make appropriate selections for such reagents from thosegiven in the definitions below, as well as from additional reagentsrecited in the specification that follows, or from those found inliterature references in the field.

“Anhydride” refers generally to compounds that will react with water orsolvent to form an acid, e.g., including carboxylic acid anhydrideshaving the formula R—C(═O)—O—C(═O)R′, wherein R and R′ are selected fromalkyl or aryl groups, as defined below, more preferably, wherein R andR′ are selected from methyl and ethyl.

“Acid” refers to any compound that contains hydrogen and dissociates inwater or solvent to produce positive hydrogen ions, as well as Lewisacids, including but not limited to acids such as hydrochloric acid,sulfuric acid, phosphoric acid, acetic acid, trihaloacetic acid (e.g.,TFA), hydrogen bromide, maleic acid, sulfonic acids such astoluenesulfonic acids and camphorsulfonic acids, propionic acids such as(R)-chloropropionic acid, phthalamic acids such as N-[(R)-1-(1-naphthyl)ethyl] phthalamic acid, tartaric acids such as L-tartaric acid anddibenzyl-L-tartaric acid, lactic acids, camphoric acids, aspartic acids,citronellic acids, BCl₃, BBr₃, and so forth. Thus, the term includesweak acids such as ethanoic acid and hydrogen sulfide; strong organicacids such as methanesulfonic acid, trifluoroacetic acid, etc.; and soforth.

“Activated methyl carbonic acid reagent” means a reagent effective toprepare a methyl carbonate ester from an alcohol. Non-limiting examplesinclude methyl chloroformate, dimethylpyrocarbonate, and the like.

“Alkyl” as used herein includes linear or branched alkyl groups havingfrom one to twelve carbon atoms, more preferably from one to eightcarbon atoms, and most preferably, from one to four carbon atoms, unlessotherwise specifically described. The term alkyl includes such groupsoptionally having up to four (more preferably 0 to 2), substituentsselected from the group of non-interfering substituents recited below.The term lower alkyl refers to alkyl groups having from one to fourcarbon atoms. When a subscript is used with reference to an alkyl orother group, the subscript refers to the number of carbon atoms that thegroup may contain. For example, the term “C₁₋₄alkyl” refers to alkylgroups of 1 to 4 carbon atoms. Alkyl moieties incorporated in otherradicals are also linear or branched, unless specifically describedotherwise. When the term alkyl is used as a prefix in conjunction withanother group, as in alkylaryl, this means the alkyl as defined above ispresent as a divalent moiety (i.e., alkylene), creating a linkage to theother, named group. Thus, alkylaryl includes benzyl and the like.

“Alkoxy” as used herein includes alkyl groups as defined above, bondedthrough an oxygen atom, i.e., —O-alkyl.

“Alkali metal salt” refers to salts formed with alkali metals,preferably salts of sodium, lithium or potassium.

“Allyl” refers to the group —CH₂—CH═CH₂, as well as such groupsoptionally having one or more (preferably 0 to 1) non-interferingsubstituents as defined below.

“Anti-oxidant” refers to a chemical compound or complex that iseffective to slow or inhibit the rate of an oxidation reaction.Exemplary anti-oxidants may include, without limitation, β-carotene,ZrO₂, ascorbic acid, aromatic amines, phenols, quinones including BHT,citric acid, ascorbic acid, vitamin E, benzoic acid, phosphoric acid,and so forth.

“Aryl” includes monocyclic or bicyclic aromatic groups having 6 to 12carbon atoms in the ring portion, i.e., phenyl and naphthyl, as well asheteroaryl groups, e.g., 4 to 7 membered monocyclic, 7 to 11 memberedbicyclic, or 10 to 15 membered tricyclic aromatic ring systems, whichhave at least one heteroatom and at least one carbon atom-containingring. Exemplary monocyclic heteroaryl groups include pyrrolyl,pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like. Exemplarybicyclic heteroaryl groups include indolyl, benzothiazolyl,benzodioxolyl, benzoxaxolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, and the like. The term “aryl”includes aryl groups optionally having up to four (preferably 0 to 2)non-interfering substituents.

“Base” when used herein includes hydroxides or alkoxides, hydrides, orcompounds such as ammonia, that accept protons in water or solvent.Thus, exemplary bases include, but are not limited to, alkali metalhydroxides and alkoxides (i.e., MOR, wherein M is an alkali metal suchas potassium, lithium, or sodium, and R is hydrogen or alkyl, as definedabove, more preferably where R is straight or branched chain C₁₋₅ alkyl,thus including, without limitation, potassium hydroxide, potassiumtert-butoxide, potassium tert-pentoxide, sodium hydroxide, sodiumtert-butoxide, lithium hydroxide, etc.); other hydroxides such asmagnesium hydroxide (Mg(OH)₂), calcium hydroxide (Ca(OH)₂), or bariumhydroxide (Ba(OH)₂); alkali metal hydrides (i.e., MH, wherein M is asdefined above, thus including, without limitation, sodium, potassium,and lithium hydrides); alkylated disilazides, such as, for example,potassium hexamethyldisilazide and lithium hexamethyldisilazide;carbonates such as potassium carbonate (K₂CO₃), sodium carbonate(Na₂CO₃), potassium bicarbonate (KHCO₃), and sodium bicarbonate(NaHCO₃); alkyl ammonium hydroxides such as n-tetrabutyl ammoniumhydroxide (TBAH); and so forth.

“Benzyl” includes the group —CH₂-phenyl, as well as such groupsoptionally containing non-interfering substituents on the methyl orphenyl portions of the benzyl, unless otherwise indicated.

“Benzyl halide” refers to a benzyl group having a halide substituent onthe alkyl portion of the benzyl group, i.e., Ph—CH₂—X, wherein X ishalide, and Ph denotes a phenyl ring as defined below.

“Benzyloxy” refers to the group —O-benzyl, wherein the benzyl moiety isas described immediately above.

“Brominated styrene-based resin” refers to one or more styrene-basedresins having one or more bromine substituents, and includes withoutlimitation, SP207 Sepabeads, SP700 Sepabeads, Diaion HP20, Diaion SP70,Diaion SP825, Diaion SP850, Diaion HP2MG methacrylate, AMBERLITE XAD4,AMBERLITE XAD7HP, AMBERLITE XAD16, and AMBERLITE XAD1600.

“Chiral amine” or “CA” as used herein refers to an amine or mixture ofamines that is optically active including dextrorotatory orlaevorotatory forms of amines. Preferably, the chiral amine comprises apure or substantially pure form of one optical isomer, but opticallyactive mixtures (i.e., mixtures that are not equimolar) are alsocontemplated. If reference is made herein to a “homochiral amine,” it isintended to encompass the broader concept of “chiral amine” as well. Forexample, these amines include, without limitation,(1R,2R)-(+)-1,2-diphenylethylenediamine, (R)-(−)-1-cyclohexylethylamine,D-threo-2-amino-1-(4-nitrophenyl)-1,3-propanediol,(1S,2S)-(+)-1,2-diaminocyclohexane, dehydroabietylamine,(1R,2R)-1,2-diaminomethylcyclohexane, cinchonidine and cinchonine

“Diastereoselective epoxidation” refers to a reaction wherein onediastereomeric epoxide is preferentially formed. The term“diastereoselective epoxidation” thus includes Sharpless epoxidationswherein epoxidation of an allylic alcohol preferentially gives oneenantiomer. However, the term “diastereoselective epoxidation” as usedherein also more broadly covers the epoxidation of a diastereomericcompound, or the epoxidation of an otherwise non-racemic compound. Theterm “diastereoselective epoxidation” is intended to includeenantioselective oxidation of olefins as described in Bonini and Righi,“A Critical Outlook And Comparison of Enantioselective OxidationMethodologies of Olefins”, Tetrahedron, Vol. 58 (2002), at pp.4981-5021, incorporated herein by reference.

“Halide” or “halo” refers to F, Cl, Br, or I, preferably Cl or I.

“Hydride reagent” refers to reagents that are capable of delivering H⁻ions. Exemplary hydride reagents include, but are not limited to,lithium aluminum hydride (LiAlH₄), sodium borohydride (NaBH₄), Red-Al®(sodium bis[2-methoxyethoxyaluminum] hydride), zinc borohydride,diisobutylaluminum hydride, sodium borohydride-cerium chloride, lithiumtriethylborohydride, lithium 9-BBN hydride, 9-BBN pyridine,borane-sulfide complex,5,5-diphenyl-2-methyl-3,4-propan-1,3,2-oxazaborolidine (Corey Reagent),lithium tri-tert-butoxyaluminum hydride, sodium cyanoborohydride,lithium tri-sec-butyl borohydride (L-Selectride®), diisobutylaluminumchloride, borane-tetrahydrofuran complex, and the like.

“Hydroperoxide” means a compound or complex comprising the hydroperoxidemoiety HO²⁻, such as compounds having the formula (R^(p)OOH), whereinR^(p) can be hydrogen (e.g., hydrogen peroxide H₂O₂), or can be analkyl, substituted alkyl, aryl, alkylaryl, substituted aryl, orsubstituted alkylaryl or other moiety (including without limitationcompounds wherein the methyl moiety of the benzyl group is optionallysubstituted). Hydroperoxides thus includeα,α-dimethylbenzylhydroperoxide, tert-butylhydroperoxide, and the like.

“Hydroxy protecting groups” means those groups that one skilled in thefield would recognize as being suitable to protect the —OH substituenton an alkyl or ringed system as described herein and which may beremoved under deprotection conditions known to those skilled in thefield as set forth, for example, in the latest edition of Greene andWuts, Protecting Groups in Organic Synthesis, incorporated herein. As anillustration, nonlimiting examples of hydroxy protecting groups includeether protecting groups (e.g. benzyl ethers, silyl ethers such astert-butyldimethylsilyl ether), esters (e.g., benzoate, acetate), andacetals (e.g., MOP).

“Homochiral diester of tartaric acid” as used herein includes singlediastereomers of alkyl tartrates including diethyl tartrate anddiisopropyl tartrate.

“Metal catalyst” refers to compounds and complexes including metallicelements that are effective as catalysts and encompasses, withoutlimitation. “transition metal catalysts.” Metal catalysts include,without limitation, titanium (IV) isopropoxide, palladium salts such aspalladium (0) catalyst, e.g., tetrakis(triphenylphosphine)palladium,copper(I)triflate, rhodium(II) acetate, Rh₆(CO)₁₆, and so forth.

“Non-interfering substituent” refers to a substituent that is bonded toa compound or complex identified herein that does not render thecompound or complex inoperable, with regard to the functionality orobject to be achieved with the particular compound or complex, and whichis compatible with the reaction sequences detailed herein. Suchsubstituents may be selected by one skilled in the field depending onthe particular reaction step and function to be achieved. Exemplarynon-interfering substituents may include without limitation groups suchas alkyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, —OR,—SR, —C(═O)R, —CO₂R, aryl, alkylaryl, C₃₋₇cycloalkyl, —NRR′₂,—NRC(═O)R′, —SO_((q))R″, —NRSO_((q))R″, —SO_((q))R″, —C(═O)NRR′, and thelike; and alkyl groups substituted with one to four (preferably 1 to 2)of halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, —OR, —SR,—C(═O)R, —CO₂R_(,) aryl, alkylaryl, C₃₋₇cycloalkyl, —NRR′₂, —NR—C(═O)R′,—SO_((q))R″, —NRSO_((q))R″, —SO_((q))R″, —C(═O)NRR′, and the like,wherein R and R′ are hydrogen, alkyl, benzyl, or aryl, as defined above,R″ is alkyl, benzyl, or aryl, as defined above, and q is 1, 2 or 3.

“Orthoformate derivatives” means reagents effective for the preparationof dioxolanes from vicinal diol moieties, or for the preparation ofimidazole rings from vicinal diamines on, for example5,6-diaminopyrimidine derivatives. Non-limiting examples includetriethylorthoformate, trimethylorthoformate, triisopropylorthoformate,diethoxymethyl acetate, and di-isopropyloxymethylacetate.

“Oxidizing agent,” or “oxidizing source” refers to any compound orcomplex that is known in the field for its effects in converting afunctional group in a molecule from a lower oxidation state to a higheroxidation state. For example, oxidizing agents may include, withoutlimitation, m-CPBA, hydrogen peroxide, AcOOH in AcOH, potassiumperoxymonosulfate, sodium periodate, sodium percarbonate, potassiumpermanganate, ruthenium oxide, and the like. Oxidizing agents may beused in the presence of one or more additives, such as KF, KHCO₃, NEt₃,AcONa, and the like. As one skilled in the field will appreciate,additives may be selected depending on the particular oxidizing agentsused and the reaction conditions.

“Per-acid” as used herein includes without limitation, magnesiummonoperoxyphthalate (MPPA), perbenzoic acids, and peracetic acid.

“Phenyl” includes phenyl rings optionally substituted with up to four(preferably 0 to 2) non-interfering substituents as defined above. Whenthe term phenyl is used as a suffix following another term, as inalkylphenyl, or alkoxy phenyl, this means the phenyl group is connectedvia a divalent moiety of the other, specifically-named group. Thus,alkylphenyl includes benzyl, phenylethyl, and the like.

“Protecting group” includes without limitation such groups as are setforth, for example, in the latest edition of Greene and Wuts, ProtectingGroups in Organic Synthesis, incorporated herein by reference.

“Reducing reagent” refers to any compound or complex that is known inthe field for its effects in converting a functional group in a moleculefrom one oxidation state to a lower oxidation state. Exemplary reducingreagents include, without limitation, NaBH₄, LAH, lithium borohydride,diisobutylaluminum hydride, sodium bis(2-methoxyethoxyaluminum) hydride,and the like. The term “reducing reagent” will include “hydridereagents” as recited above.

“Strong non-nucleophilic base” means a non-aqueous base that does notact as a nucleophile, such as sodium or potassiumbistrimethylsilylamide, lithium diisopropylamide, sodiumbistrimethylsilylamide, potassium, lithium, or sodium hydride.

“Tertiary amine base” means a trialkylamine, such as triethylamine,N,N-dimethylethylamine, diisopropylethylamine (Hunig's base) ortetramethylenediamine (TMEDA), or a nitrogen containing heterocycle,such as pyridine.

“Trimethylsilylating reagent” means a reagent effective to prepare atrimethylsilyl ether from an alcohol. Non-limiting examples includechlorotrimethylsilane, trimethylsilyl trifluoromethanesulfonate, and thelike.

Additionally, it should be understood in the methods of preparation andclaims herein, that the pronoun “a”, when used to refer to a reagent,such “a base”, “a metal catalyst”, “a hydroperxoide” and so forth, isintended to mean “at least one” and thus, include, where suitable,single reagents as well as mixtures of reagents. Thus, for example, areaction step involving use of “a base”, or for example, involving useof “a base selected from one of potassium hydroxide, potassiumtert-butoxide, potassium tert-pentoxide, sodium hydroxide, sodiumtert-butoxide, lithium hydroxide,” encompasses use of potassiumhydroxide as a base, or, where appropriate, mixtures of potassiumhydroxide plus one or more additional bases set forth in the group fromwhich a selection may be made. One skilled in the field may makeappropriate selections given the reactions steps and conditions andresult to be achieved.

Methods of Preparation

The compound entecavir and novel intermediates therefor may be preparedby the exemplary processes described in the following reaction Schemes.Exemplary reagents and procedures for these reactions appear hereinafteror are described above. Starting materials are commercially available orcan be readily prepared by one of ordinary skill in the art. Solvents,temperatures, pressures, starting materials having the desired groups,and other reaction conditions, may be readily selected as appropriate byone of ordinary skill in the art.

Process A of the invention comprises preparation of the ester of formula66, a preferred intermediate or starting material for preparingentecavir 21. In the ester of formula 66, R is a C₁ to C₄ alkyl orbenzyl, preferably methyl; R^(a) is allyl, phenyl, C₁ to C₆ alkylphenylor C₁ to C₆ alkoxyphenyl, more preferably R^(a) is selected from phenyl,C₁ to C₃ alkylphenyl, and C₁ to C₃ alkoxyphenyl; and R^(b) is C₁ to C₆alkyl, preferably methyl. The ester can be prepared by any method thatprovides the ester in high diastereomeric and enantiomeric purity. Apreferred procedure is shown in Scheme 1, wherein sodiumcyclopentadienide 62 is treated with a silylating reagent, e.g.,R^(a)(R^(b))₂SiY, wherein Y is a leaving group, e.g.,phenyldimethylchlorosilane wherein R^(a) is phenyl, R^(b) is methyl, andY is Cl. The reaction may be carried out in a solvent such as MTBEand/or THF. The resulting silane moiety serves as a masked hydroxy groupthat can be unveiled later in the synthetic process. The product of thesilylation reaction can then be elaborated using a 2+2 cycloadditionreaction with ketene, e.g., generated from dichloroacetyl chloride andan appropriate base (e.g., Et₃N, NaOH, KOH, NaHCO₃, KHCO₃, Na₂CO₃,K₂CO₃, TBAH, etc.), to give the cyclobutanone of formula 63. Thecyclobutanone can then be opened with a suitable base (e.g., Et₃N, NaOH,KOH, NaHCO₃, KHCO₃, Na₂CO₃, K₂CO₃, TBAH, etc.), and the resultingintermediate reduced with a suitable reducing agent, e.g., NaBH₄, toprovide the carboxylic acid of formula 64.

Resolution of the enantiomers of the carboxylic acid 64 can beaccomplished by salt formation with chiral amines (CAs) and separationof the resulting diastereomeric salts. A diastereomeric mixture ofammonium salts of the carboxylic acid of formula 64 is preferablyprepared using R,R-(−)-2-amino-1-(4-nitrophenyl)-1,3-propanediol. Thoseof ordinary skill in the art will appreciate that other chiral aminescan be used to achieve the resolution of the enantiomers of thecarboxylic acid of formula 64. These amines include, for example,(1R,2R)-(+)-1,2-diphenylethylenediamine, (R)-(−)-1-cyclohexylethylamine,D-threo-2-amino-1-(4-nitrophenyl)-1,3-propanediol,(1S,2S)-(+)-1,2-diaminocyclohexane, dehydroabietylamine,(1R,2R)-1,2-diaminomethylcyclohexane, cinchonidine and cinchonine.

Separation of the resulting diastereomeric salts can be accomplished byany separation procedure known to those of ordinary skill in the art,such as chromatography or crystallization. Separation of thediastereomeric salts is preferably effected by crystallization. Forexample, the diastereomerically enriched ammonium salt of formula 65A(where the chiral amine used isR,R-(−)-2-amino-1-(4-nitrophenyl)-1,3-propanediol) can be isolated bycrystallization from EtOH. The ammonium salt of formula 65A isolated bythis procedure can have a chemical purity of 98% and 98% de Conversionof the ammonium salt of formula 65A to the ester of formula 66 (R isalkyl) can be accomplished by heating in an acidic solution, e.g., MeOHand an appropriate acid, such as sulfuric acid or p-toluenesulfonicacid, or HCl in methylene chloride. Alternatively, compound 65A can beconverted into a free acid which is subjected to esterification withalcohol, e.g., MeOH, in the presence of PTSA, at refluxing conditions,to provide compound 66.

Process B of the invention comprises preparing entecavir 21, viacoupling an epoxide of formula 72, with a substituted guanine derivativeto prepare a carbocyclic nucleoside, the compound of formula 73, whichis then elaborated to the compound 21. One embodiment of Process B isdepicted in Scheme 2. In this process, a preferred starting material forthe epoxide of formula 72 is an ester of formula 66 (which can beprepared as described in Scheme 1). The compound of formula 66 can beepoxidized and the ester group can be reduced to furnish thecyclopentane epoxide of formula 72 in high diastereomeric purity. Forexample, the compound of formula 66 can serve as starting material for adiastereoselective epoxidation reaction. In one embodiment, thecyclopentane epoxide of formula 72 is formed after the epoxidation andreduction steps in at least 96% de. The diastereoselective epoxidationcan be effected with a pera acid or with a pera homochiral diester oftartaric acid, a hydroperoxide, and a metal catalyst, such as atransition metal catalyst. Preferably, the homochiral ester is DIPT, thehydroperoxide is TBHP or CHP, and the metal catalyst is titanium (IV)isopropoxide. Preferably, the reaction is carried out in an inertsolvent such as dry DCM or toluene. Methods suitable for effecting thecatalytic epoxidation reactions are described in U.S. Pat. Nos.4,471,130; 4,594,439; and 4,900,847, incorporated herein by reference.After workup, the crude product can be carried on in the synthesiswithout further purification.

The crude product from the epoxidation reaction is treated with areducing reagent that selectively reduces the ester group to an alcohol,such as, e.g., NaBH₄, LAH, lithium borohydride, diisobutylaluminumhydride, sodium bis(2-methoxyethoxyaluminum) hydride, and the like. Inone embodiment, the reducing agent used in the reaction is NaBH₄ in IPA.The reduction provides the cyclopentane epoxide having the formula 72.

The cyclopentane epoxide of formula 72 can then be heated, for example,to about 80° C. with an alkali metal salt, e.g, a lithium salt, of thepurine compound of formula 28, wherein X is Cl, I, or benzyloxy (BnO) ina dipolar aprotic solvent such as DMF to prepare the compound of formula73. For example, the lithium salt of 2-amino-6-O-benzyloxypurine isprepared by treatment with base such as LiOH or LiH. This couplingreaction to prepare the carbocyclic nucleoside is advantageous in thatit provides a high N-9 to N-7 ratio (e.g., N-9:N-7>20:1), allowsconvenient workup and purification procedures, and provides usefulyields of the compound of formula 73. For example, after water workup,the crude product of the coupling reaction of the purine compound offormula 28 wherein X is BnO, and the cyclopentane epoxide of formula 72,can be purified by simple recrystallization from a solution ofEtOAc-hexanes to provide the compound of formula 73 in 65% yield.

The compound of formula 73, wherein X is BnO, can then be converted tothe compound of formula 71 by converting the vicinal diol moiety to analkene. Analogously, the compound of formula 73, wherein X is Cl or I,can be converted to compound 92 by converting the vicinal diol moiety toan alkene. In one embodiment, the vicinal diol of the compound offormula 73 is converted to an alkene as in compounds 71 and 92, by atwo-step procedure. In the first step, the compound of formula 73 istreated with an orthoformate derivative, such as DEMA, DiPMA, TiPOF,TEOF, or TMOF, in the presence of an acid such as PPTS or TFA. Thereaction is preferably carried out in an inert solvent such as DCM,toluene, or tert-butyl methyl ether, at room temperature for asufficient amount of time to form a product comprising a diastereomericmixture of dioxolanes. In the second step, the diastereomeric mixture ofdioxolanes is heated with acetic anhydride, preferably in the presenceof acetic acid and an antioxidant, e.g., BHT, to form the alkene. Inembodiments wherein X is BnO, the crude product from the aceticanhydride treatment can then be heated with acid such as aqueous mineralacid or aqueous organic acid, e.g., HCl or MSA, to hydrolyze the6-benzyloxy group (as well as an 2-N-acetyl group formed in the aceticanhydride treatment) to provide the methylene compound of formula 71, orits salts (e.g., MSA or HCl salts). The intermediates of formulas 71 and92 can be isolated in the form of a salt by treatment with an acid suchas HCl, MSA, (1S)-(+)-10-camphorsulfonic acid, (R)-chloropropionic acid,N-[(R)-1-(1-naphthyl) ethyl] phthalamic acid, L-tartaric acid,dibenzyl-L-tartaric acid, L-lactic acid, (1R,3S)-camphoric acid,L-aspartic acid, (S)-citronellic acid, etc.

Preparation of the final compound 21 from compound 71 can then beaccomplished by converting the silane moiety to a hydroxy moiety. Thisconversion can be achieved via protodesilylation of the silane moietyfollowed by oxidation with an oxidizing source, such as, for example,hydrogen peroxide. The protodesilylation step can be achieved viareaction with boron trifluoride-acetic acid complex, or a Bronsted acidsuch as TFA, MSA, FMSA, or tetrafluoroboric acid in an inert solvent,e.g., DCM. Alternatively, protodesilylation can be achieved with a baseor acid as described below in Scheme 6. Upon debenzylation (which may,in some embodiments, be achieved in the protodesilyation step (e.g.,when MSA or FMSA are used), there is provided the protodesilylatedintermediate of formula 91

The protodesilylated intermediate 91 can then be oxidized. The oxidizingagent(s) can be selected in view of the reagent used to achieveprotodesilyation. For example, when boron trifluoride-acetic acidcomplex is used, the compound can be oxidized with hydrogen peroxide andKHCO₃, to provide the target compound of formula 21, and when a Bronstedacid is used, compound 91 may be oxidized with hydrogen peroxide, KHCO₃,and KF. Other acids and oxidizing agents that may be useful may berecited above. Alternatively, conversion of the silyl moiety to ahydroxy group may be achieved as described in Scheme 6, below, andadditional methods that may be useful for the transformation of thesilyl group to the hydroxy group are described in Fleming, I.(Chemtracts-Organic Chemistry 1996, 9, 1-64) and Jones, G. R. et al.(Tetrahedron, 1996, 52, 7599-7662), both of which are hereinincorporated by reference. The compound of formula 21 can be furtherpurified, for example, by recrystallization from water, and/or via resinpurification as described below in Process K.

In alternate embodiments of Process B, the purine 28, coupled withcyclopentane epoxide 72 to give compound 73, is other than2-amino-6-benzyloxypurine, such as 2-amino-6-chloropurine or2-amino-6-iodopurine. In this embodiment, compound 73 is upon treatmentwith the orthoformate, acid, etc., converted to compound 92, which uponprotodesilylation and oxidation is converted to compound 93. In thisinstance, wherein 2-amino-6-chloropurine or 2-amino-6-iodopurine isused, an additional treatment with aqueous base or acid (preferablyaqueous base) may be utilized to convert the halo group of compound 93into the 6-oxo moiety. For example, aqueous NaOH solution may be used toconvert the compound of formula 93 to the compound of formula 21.

The ester of formula 66 can also be converted to the compound of formula21 by the methods of Process C. One embodiment of Process is depicted inScheme 3. In contrast to Process B, the epoxidation reaction of thecyclopentane in Process C is performed after the ester moiety has beenreduced. In Process C, the primary alcohol moiety of the ester offormula 66 (R=alkyl) is protected with a protecting group such as a MOPby treatment with 2-methoxypropene and a catalytic amount of an acid,such as PPTS, in an insert solvent such as toluene, to yield thecompound of formula 74. The carboxylic ester moiety of 74 can be reducedwith a hydride reagent, preferably Red-Al® or LAH. In one embodiment,the ester moiety of 74 is reduced, preferably after the addition of asuitable base, such as with a tertiary amine base, e.g., Et₃N, in thesame reaction vessel to give the compound of formula 75. In anotherembodiment, the ester moiety of 74 is reduced with a hydride reagentafter workup, to give compound 75. The resultant alcohol moiety of thecompound of formula 75 is first protected with a protecting group thatis resistant to hydrolysis conditions that are then used to remove theMOP group. For example, the alcohol moiety of the compound of formula 74can be treated with a base (e.g., KOtBu, KHMDS, NaH, phase-transfercatalyst conditions using 50% NaOH), and a benzyl halide, e.g., benzylbromide or benzyl chloride, preferably in solvent such as toluene orTHF, to protect the alcohol moiety as a benzyl ether. The MOP acetal canthen be hydrolyzed by addition of aqueous acid, such as 1 N HCl, to givethe allylic alcohol of formula 76. Other protecting groups known in thefield may be found in the literature, such as Greene and Wuts, citedabove in the general definitions herein.

The allylic alcohol of formula 76 serves as starting material for adiastereoselective epoxidation reaction, wherein the product, thecyclopentane epoxide of formula 77, is formed in high diastereomericpurity. For example, the epoxidation can be effected using a homochiraldiester of tartaric acid, a hydroperoxide, and a metal catalyst, such asa transition metal catalyst. Alternately, the diastereoselectiveepoxidation may be performed with a peracid, such as MPPA, as describedin Scheme 14 and Example 12. Preferably, diastereoepoxidation isperformed with the homochiral ester DIPT, the hydroperoxide TBHP or CHP,and the metal catalyst Ti(O-iPr)₄. Preferably, the reaction is carriedout in an inert solvent such as toluene, methylene chloride, etc. In oneembodiment, the cyclopentane epoxide of formula 77 is formed in at least96% de.

The cyclopentane epoxide of formula 77 can then be reacted (e.g., atelevated temperature, e.g., preferably at about 80° C.) with an alkalimetal salt of purine compound of formula 28, wherein X is Cl, I or BnO,in a dipolar aprotic solvent such as DMF to prepare the compound offormula 78. Preferably, the purine compound of formula 28 is2-amino-6-benzyloxypurine. The 2-amino-6-benzyloxypurine is commerciallyavailable or can be prepared from 6-chloroguanine and the sodium salt ofbenzyl alcohol (e.g., upon treatment with NaOH in benzyl alcohol,toluene, and MeOH, or upon treatment with the sodium salt of benzylalcohol, benzyl alcohol, in EtOH/water.). The alkali metal salt can begenerated in situ by reaction of 2-amino-6-O-benzyloxypurine with, forexample, LiH or LiOH. The crude compound of formula 78, wherein X isbenzyloxy, can be isolated and purified. For example, the crude compound78 can be isolated upon addition of IPA and water, then purified byrecrystallization with solvents or solvent mixtures known in the field.

The compound of formula 78 can then be converted to the compound offormula 21 using various reaction sequences analogous to those used toconvert the compound of formula 73 to the compound of formula 21 inProcess B, which are further described in Schemes 4, 5 and 6, below.

Scheme 4 describes a process for converting compound 78A (compound 78wherein X is OBn), to the compound of formula 21. Compound 78A can betreated with an orthoformate derivative, such as DEMA, DiPMA, TMOF,TiPOF, TEOF, etc., preferably in an inert solvent such as toluene, DCM,MTBE etc., as described in Scheme 2, in the presence of a catalyticamount of an acid such as TFA or PTSA, or an acid catalyst such as PPTS,etc., to form a product comprising a diastereomeric mixture ofdioxolanes, e.g., compounds 101 and 103. The diastereomeric mixture ofdioxolanes 101 and 103 can be heated with acetic anhydride preferably inthe presence of acetic acid and an anti-oxidant, such as BHT, to formalkene having the formula 105. The crude product 105 can then be heatedwith acid, such as with aqueous HCl or MSA, in an appropriate solventsuch as MeOH and water, to hydrolyze the 6-benzyloxy and N-acetyl groupsand provide the methylene compound of formula 79. The intermediate 79can be isolated in the form of a salt by treatment with an acid such asHCl, MSA, (1S)-(+)-10-camphorsulfonic acid, (R)-chloropropionic acid,N-[(R)-1-(1-naphthyl) ethyl] phthalamic acid, L-tartaric acid,dibenzyl-L-tartaric acid, L-lactic acid, (1R,3S)-camphoric acid,L-aspartic acid, (S)-citronellic acid, etc. In one embodiument,intermediate 79 or salts thereof are further purified byrecrystallization, e.g., intermediate 79 salts thereof are treated withNaOH in an organic solvent and crystallized before proceeding to thenext step.

Preparation of the final compound of formula 21 from compound 79, orsalts thereof, can then be accomplished by converting the silane moietyto a hydroxy moiety. This conversion can be achieved viaprotodesilylation of the silane moiety with reagent(s) selected toprovide the intermediate compound 91, followed by oxidation.Protodesilylation may be achieved with boron trifluoride-acetic acidcomplex or a Bronsted acid in insert solvent, e.g., MSA in methylenechloride. Oxidation may be carried out as described in Scheme 2, usingoxidizing agents and additives appropriately selected, i.e., dependingon the reagent used for protodesilylation and the oxidizing agent, e.g.,in the case of a Bronsted acid, hydrogen peroxide in the presence ofKHCO₃ and KF may be used, to provide compound 21. Compound 21 can befurther purified, for example, by recrystallization from water, and/orvia resin purification as described below in Process K.

Scheme 5 describes an alternate process for making compound 21, whereinthe purine 28 of Scheme 3 is 2-amino-6-chloropurine or2-amino-6-iodopurine, such that coupling with cyclopentane epoxide 77,yields compound 78B (compound 78 wherein X is Cl or I). As in Scheme 4,compound 78B can be treated with an orthoformate derivative to form aproduct comprising a diastereomeric mixture of dioxolanes 102 and 104,which can be heated with acetic anhydride, preferably in the presence ofacetic acid and an anti-oxidant, e.g., BHT, to form alkene 106. Theproduct 106 can then be heated with acid, such as HCl or MSA, asdescribed in Scheme 4, to hydrolyze the acyl group and provide compound94, or salts thereof, which retain the 6-position X group.Protodesilylation, debenzylation, and oxidation as described in Scheme4, provides the intermediate compound 95. Compounds 94 and 95 can beisolated in the form of their salts by treatment with acid(s) aspreviously described for compound 79. Compound 95 can then be treatedwith aqueous base or acid (preferably, an aqueous base) to convert thehalo group of compound 95 into the 6-oxo moiety of compound 21. As maybe appreciated, with Process C(b) an additional step may be used for theconversion of compound 78 to 21, as compared with Process C(a).

Scheme 6 shows an alternate process for preparing compound 21 fromcompound of formula 79, which is shown in Scheme 4. As compared withScheme 4, in this scheme a different base or acid is used to achieve theprotodesilylation, followed by oxidation and debenzylation to convertcompound 79 to compound 21. Compound 79 is treated with a base such as ahydroxide, e.g., NaOH or KOH, or alkoxide such as KOtBu, in a polaraprotic solvent such as DMF, DMSO, or NMP, or with a strong acid such asTFA, and heated at a time and temperature sufficient to achieve theconversion to intermediate 110. Compound 110 can then be oxidized withhydrogen peroxide in the presence of KHCO₃ and KF in a solvent such asMeOH, to provide intermediate 114. Intermediate 114 can be debenzylatedupon treatment with a Lewis acid such as BCl₃, BBr₃, etc., or a Bronstedacid such as MSA, TFMSA, etc., in solvent such as DCM, and the reactionmixture can be neutralized with base such as NaOH, to provide compound21. Compound 21 can be further purified by recrystallization from waterand/or resin purification as described below.

In Process D of the invention, the ester of the formula 66 (Scheme 1)can be converted to the compound of formula 21 using different syntheticmethods. In Process D, the ester of formula 66 is aminohydroxylated toprovide a chiral oxazolidinone of the formula 67. After a series ofsynthetic steps, a pyrimidine carbocyclic nucleoside, the compound offormula 70 is prepared. The pyrimidine carbocyclic nucleoside can beelaborated to a purine containing compound, the methylene compound offormula 71 which is subsequently converted to the compound of formula 21by, for example, the oxidation procedure described in the final steps ofProcesses B and C. One embodiment of Process D is depicted in Scheme 7.

Aminohydroxylation conditions are used to convert the ester of formula66 to the oxazolidinone of formula 67. Amino hydroxylation proceduresare analogous to those described in Li, G.; Angert, H.; Sharpless, K. B.Angew. Chem. Int. Ed., (1996), at 2813. Preferably, theaminohydroxylation conditions comprise treatment with: the reagentprepared from the treatment of methyl carbamate with tert-butylhypochlorite and sodium hydroxide [i.e., MeOC(O)N(Cl)Na]; and potassiumosmate in an inert solvent such as DCM. Alternative reagents includeEtOC(O)N(Cl)Na and BnOC(O)N(Cl)Na. Preferably, the chiral oxazolidinoneof formula 67 is formed in at least 96% de.

The primary alcohol moiety of the oxazolidinone of formula 67 can thenbe converted to an iodide. For instance, in one preferred procedure, thecompound of formula 67 is treated with trifluoromethanesulfonicanhydride (Tf₂O) in the presence a tertiary amine base such as pyridine,and subsequently treated with an iodide salt, e.g, lithium iodide. Theresulting iodide of the formula 68 can then be converted to a methylenecompound of formula 69 by a two step procedure. In the first step theiodide of formula 68 is treated with zinc powder and acetic acid. Theester moiety of the resulting intermediate can then be reduced to aprimary alcohol in the second step by a hydride reagent such as sodiumbis[2-methoxyethoxyaluminum] hydride to give the amine of the formula69.

The amine of the formula 69 is subsequently reacted with a substitutedchloropyrimidine. The amine can be condensed, for example, with2-amino-6-chloro-5-nitro-4-(3H)-pyrimidinone in the presence of atertiary amine base, preferably triethylamine, in refluxing n-butanol togive a pyrimidine compound of formula 70. The pyrimidine compound offormula 70 can then be converted to a purine derivative by a two stepprocedure. In the first step, the nitro moiety of the pyrimidine isreduced with, for example, sodium dithionite, to give atriaminopyrimidine intermediate. Alternative reducing agents andconditions that can also successfully reduce the nitro group includeNaBH₄/THF, NaBH₄-BiCl₃, Sn/HCl, SnCl₂, Mg/(NH₄)₂SO₄/MeOH, CuBr.SMe₂,TiCl₂(Cp)₂/Sm, iron and nickel catalyzed procedures. In the second step,treatment of the triaminopyrimidine intermediate with formic acid,hydrochloric acid, and an orthoformate derivative, e.g.,triethylorthoformate, effects cyclization and provides the methylenecompound of formula 71. The methylene compound of formula 71 can beconverted to the compound of formula 21 by the oxidation proceduredescribed in the final steps of Processes B and C.

Process E of the invention comprises using an alternative carbocyclicsugar precursor, an allylic alcohol of the formula 16, to prepare thecompound of formula 21. Process E is similar to Processes B and C as allthree processes use cyclopentane epoxide intermediates to accomplish acoupling reaction with a guanine precursor. In a first embodiment ofProcess E, the protecting group that serves to protect the secondaryalcohol of the cyclopentane ring of 16 is a benzyl/substituted benzylether, while in a second embodiment a silyl ether protecting group(R^(c)R^(d) ₂Si) protects the same secondary alcohol. (In this instance,R^(c) is linear or branched C₁ to C₄ alkyl, or phenyl, and R^(d) islinear or branched C₁ to C₃ alkyl.) A preferred benzyl ether protectinggroup is benzyl ether, per se, while a preferred silyl ether istert-butyldimethyl silyl ether. The difference in these protectinggroups changes the identity of the intermediates for the differentembodiments of Process E. Certain embodiments of Process E are depictedin Scheme 8.

In one embodiment of Process E, the allylic alcohol of formula 16 isobtained through a reduction of the ester of the formula 7. The ester ofthe formula 7, wherein R and R′ are as defined above, can be obtained byProcesses E(a)-E(d) that are described below. The ester of formula 7 canbe reduced with hydride reagents that selectively effect 1,2-reductionof the ester. For example, in one embodiment, diisobutylaluminum hydridereduces the ester group and provides the allylic alcohol of the formula16.

The allylic alcohol of formula 16 can then be diastereoselectivelyepoxidized. For example, the epoxidation can be accomplished using ahomochiral diester of tartaric acid, a hydroperoxide, and a metalcatalyst, such as a transition metal catalyst, to yield a cyclopentaneepoxide of the formula 17. In one embodiment, the homochiral diester is(−)-diethyl tartrate [(−)-DET], the hydroperoxide is TBHP or CHP, andthe metal catalyst is titanium (IV) isopropoxide. Preferably, thereaction is carried out in an inert solvent such as DCM.

The epoxide of formula 17 can be subsequently coupled to an alkali metalsalt (e.g., lithium) of a purine compound of formula 28, wherein X isCl, I or BnO, in a dipolar aprotic solvent such as DMF to afford thecompound of formula 18. Preferably the coupling of the cyclopentaneepoxide of the formula 17 is conducted with the lithium salt of2-amino-6-benzyloxypurine. The compound of formula 18, wherein X isbenzyloxy, can be purified by crystallization from solvents such asethyl acetate and hexanes. Typically the yield of the coupling stepafter purification is at least 75%.

The vicinal diol moiety of the compound of formula 18 can then beconverted to an alkene moiety. For example, the diol moiety can beconverted to an alkene by procedures that are analogous to those used inProcesses B and C. Accordingly, in one embodiment, the compound offormula 18 can be treated with an orthoformate derivative, e.g,trimethyl orthoformate, in the presence of a catalytic amount of an acidsuch as TFA or PTSA, or acid catalyst such as PPTS. The resultingmixture of dioxolanes (preferably as a crude mixture) is heated with amixture of acetic anhydride and optionally acetic acid to provide themethylene compound of formula 19. Alternatively, this reaction can beperformed in the presence of antioxidant such as BHT as describedpreviously. In the instance of the second embodiment of Process E (wherethe secondary alcohol of 18 is protected by a silyl ether group), thesilyl ether protecting group is simultaneously hydrolyzed during theacetic anhydride/acetic acid treatment step (i.e., R′ is H in themethylene compound of formula 19).

In embodiments of the Process E, wherein X is OBn, the 6-O-benzyloxygroup can be hydrolyzed (as well as any pendant 2-acetamide group formedfrom the acetylation of the 2-amino group of the purine during theacetic anhydride treatment step) by heating the compound of formula 19with aqueous mineral acid, such as 2 N HCl to give the methylenecompound of formula 20. In embodiments of Process E, wherein X is Cl orI, the 6-halo group can be hydrolyzed by treatment with aqueous acid orbase (e.g., aqueous hydroxide solution). Removal of the remaining benzylether protecting group(s) on the cyclopentane ring, such as by borontrichloride treatment in an inert solvent, e.g., DCM, provides thecompound of formula 21.

The ester of formula 7 can be prepared by methods that yield scaleablequantities of enantiomerically pure ester. In Process E(a) the ester offormula 7 can be prepared from a diol of the formula 1, which isprepared according to procedures described in J. Am. Chem. Soc. 1989,3456 and J. Am. Chem. Soc. 1996, 9526. One embodiment of Process E(a) isdepicted in Scheme 9.

The diol of formula 1 can be acetylated with, for example, aceticanhydride and pyridine to provide a diacetate of the formula 2.Selective enzymatic hydrolysis of one of the prochiral acetate functionsof the diacetate provides enantiomerically pure monoacetate of theformula 3. Preferably the enzyme used is a hydrolase such as LipasePS-30 from Pseudomonas cepacia or Pancreatin. Preferably theenantiomeric excess of the product monoacetate of formula 3 is at least96% ee, more preferably at least 98% ee. In some embodiments the enzymeis immobilized on a support, e.g., polypropylene, to aid in recovery ofthe enzyme and facilitate reaction workup. The reaction is typicallycarried out in a mixture of a buffer and an organic solvent, preferablyhaving a buffer/organic solvent ratio of about 3/1 to about 20/1,preferably about 9:1. The buffer is selected to have a buffering rangeeffective to maintain the pH of the reaction mixture in a rangeeffective to support enzyme catalysis, such as at about pH=7. Forexample, 25 mM potassium phosphate buffer can be used. In one embodimentthe organic solvent is toluene.

The monoacetate of formula 3 can be coupled tophenylsulfonylnitromethane to provide a compound of formula 4. Thecoupling is preferably catalyzed by a palladium (0) catalyst such astetrakis(triphenylphosphine)palladium in THF with a tertiary amine base,such as triethylamine. The secondary hydroxyl group of the compound offormula 4 is protected using a benzyl halide and a non-nucleophilicstrong base such as sodium hydride to give the dibenzyl compound offormula 5. The dibenzyl compound of formula 5 can be oxidized, such aswith potassium peroxymonosulfate: tetrabutyl ammonium, preferably in asolvent mixture of DCM and MeOH. The intermediate carboxylic acid can beesterified, for example, by directly heating with an alcohol (ROH),preferably MeOH, and sulfuric acid in the same reaction vessel to affordthe ester of formula 6.

Isomerization of the double bond provides the desired ester of formula7. The isomerization can be accomplished by heating the crude ester offormula 6 under basic conditions. Preferably the basic conditionscomprise heating the ester with a sodium alkoxide/alcohol mixture. Aswill be apparent to those of ordinary skill in the art, the alkoxide andalcohol mixture are preferably selected so that transesterification ofthe ester moiety during the isomerization is minimized or eliminated. Byway of example, if a methyl ester is desired for the compound of formula7 (i.e., R=methyl) then the basic conditions chosen for theisomerization are preferably sodium methoxide/MeOH. The ester of formula7 can be purified by recrystallization from a mixture of solvents suchas hexanes and tert-butyl methyl ether.

In Process E(b), the ester of formula 7 is prepared using alternativesynthetic methods. One embodiment of Process E(b) is depicted in Scheme10. The diol of formula 1 is selectively acetylated using a hydrolaseenzyme, such as Lipase PS-30 or Pancreatin to generate enantiomericallyenriched monoacetate compound of formula 13. Here again, the enzyme canbe immobilized on a support. The acetylation reaction can be carried outin an organic solvent such as mixture of heptane: methyl tert-butylether. Preferably, the enantiomeric excess of the product, themonoacetate of formula 13 is at least 96% ee, more preferably at least98% ee.

The monoacetate of formula 13 can be converted to the alkyl carbonate ofthe formula 14, wherein R⁴ is preferably C₁ to C₆ alkyl, benzyl, phenyl,or phenyl substituted by C₁ to C₆ alkyl, for example, by treatment withan activated alkyl carbonic acid derivative, such as methylchloroformate, dimethyl carbonate, etc. Preferably, the conversion isaccomplished with methyl chloroformate and a tertiary amine base, e.g.,pyridine, in an inert solvent, preferably DCM.

The alkyl carbonate of formula 14 can then be coupled withphenylsulfonylnitromethane to provide a compound of formula 15. Thecoupling is preferably catalyzed by a Pd(0) catalyst, e.g.,tetrakis(triphenylphosphine)palladium,tris(dibenzylideneacetone)dipalladium(0),bis(dibenzylideneacetone)-palladium(0).CHCl₃, in a solvent, e.g., THF,with a tertiary amine base, such as triethylamine. The compound offormula 15 is treated with a base, e.g., potassium carbonate in MeOH, toremove the acetate group and provide the compound of formula 4. Thesecondary alcohol moiety can be protected as a benzyl ether group byreacting the compound of formula 4 with a benzyl halide, e.g., benzylbromide, preferably in the presence of a strong non-nucleophilic base,e.g., sodium hydride, to give the compound of formula 5. The compound offormula 5 can be converted to the ester of formula 7 by the methodsalready described in Process E(a).

Alternatively, Process E(c) can be used to prepare the ester of formula7 (where R″ is benzyl). One embodiment of Process E(c) is depicted inScheme 11. A cyclopentane epoxide of the formula 8 serves as the chiralstarting material. The cyclopentane epoxide of formula 8 can be preparedaccording to the procedure described in U.S. Pat. No. 5,206,244, thedisclosure of which is incorporated by reference as if fully set forthherein. An allylic alcohol of formula 9 is prepared by heating theepoxide of formula 8 with a strong non-nucleophilic base, e.g., lithiumhexamethyldisilazide in THF. After aqueous workup, the allylic alcoholof formula 9 can be used without further purification. Here again, theallylic alcohol moiety can be converted to the alkyl carbonate group,wherein R⁴ is preferably C₁ to C₆ alkyl, benzyl, phenyl, or phenylsubstituted by C₁ to C₆ alkyl, for example, by treatment with anactivated alkyl carbonic acid derivative, such as methyl chloroformate,dimethyl carbonate, etc to give the alkyl carbonate of the formula 10.In one embodiment, the allylic alcohol of formula 9 is stirred withmethyl chloroformate and a tertiary amine base, preferably pyridine, inan inert solvent, e.g, DCM, to give a methyl carbonate. The crude alkylcarbonate can be directly coupled to phenylsulfonylnitromethane in THFto provide a compound of formula 5. The coupling of the alkyl carbonatecompound is preferably catalyzed by a palladium (0) catalyst such astetrakis(triphenylphosphine)palladium in THF with a tertiary amine base,e.g. triethylamine. The compound of formula 5 can be converted to theester of formula 7 by the methods described in Process E(a).

Process E(d) can also be used to prepare the ester of formula 7, whereinR′ is benzyl or silyl. Embodiments of Process E(d) are depicted inScheme 12. In the process, the allylic alcohol of formula 9 is oxidizedwith an oxidizing reagent such as pyridinium dichromate (PDC),pyridinium chlorochromate, manganese dioxide, and the like, in an inertsolvent, preferably DCM, to afford the cyclopentenone of formula 80. Thecyclopentenone is reduced with hydride reagents that selectively effecta 1,4-hydride addition. Suitable reducing conditions include, forexample, treatment with lithium tri-sec-butylborohydride in THF. Theintermediate from the reduction is trapped with an activatedtrifluoromethanesulfonic acid derivative such as N-phenyltriflimide toprovide the triflate of the formula 81. An alkyloxycarbonyl group isthen inserted onto the ring using, for example, a palladium catalyzedcarbonyl insertion reaction to prepare the ester of formula 7.Preferably the insertion reaction is performed in a mixture of DMF andan alcohol, preferably MeOH, with an excess amount of a tertiary aminebase, such as triethylamine. A preferred catalyst for the reaction is apalladium (0) catalyst, e.g., tetrakis(triphenylphosphine)palladium.

In embodiments of Process E(d) wherein R′ is a benzyl or substitutedbenzyl group, the allylic alcohol 9 can be prepared as described inProcess E(c) from the cyclopentane epoxide of formula 8. In embodimentsof Process E(d) wherein R′ is a silyl ether protecting group, theallylic alcohol can be prepared in a two-step procedure from themonoacetate of formula 3 (which can be prepared as described in ProcessE(a)). The secondary alcohol moiety of the monoacetate of formula 3 isreacted with a silylating reagent R^(c)R^(d) ₂SiY, wherein Y is asuitable leaving group, e.g., chloride, triflate, and the like. In oneembodiment, the secondary alcohol is protected as atert-butyldimethylsilyl ether using tert-butyldimethylsilyl chloride(TBSCl) in the presence of pyridine in an inert solvent such as DCM togive a compound of formula 22. The acetyl group of the compound offormula 22 is hydrolyzed by using a base e.g., potassium carbonate in analcohol solvent, to give the allylic alcohol of formula 9.

Process F of the invention includes preparation of a suitablysubstituted cyclopentanol of formula 37, and coupling of thecyclopentanol with a guanine precursor, such as 2-amino-6-iodopurineunder Mitsonobu conditions to give a carbocyclic nucleoside, themethylene compound of formula 38. The methylene compound of formula 38can then be elaborated to the compound of formula 21. One embodiment ofProcess F is depicted in Scheme 13.

The cyclopentenone of formula 32 (also known as4-(S)-hydroxy-2-cyclopenten-1-one) serves as starting material forProcess F. The cyclopentenone can be obtained according to proceduresdescribed in Khanapure, S.; Najafi, N.; Manna, S.; Yang, J.; Rokash. J.J. Org. Chem., 1995, 60, 7448. The alcohol moiety of the cyclopentenoneof formula 32 can be protected as a silyl ether using the silylatingreagent of the formula R^(c)R^(d) ₂SiY (wherein R^(c), R^(d) and Y areas defined in Process E and E(d)). For example, the alcohol moiety ofthe cyclopentenone of formula 32 can be protected as atert-butyldimethylsilyl ether using tert-butyldimethylsilyl chloride(TBSCl), a tertiary amine base such as N,N-dimethylethylamine, and acatalytic amount of 4-N,N-dimethylaminopyridine in an inert solvent suchas DCM to give the cyclopentenone of formula 33. The cyclopentenone offormula 33 can then be treated with a Grignard reagent prepared from a(halomethyl)dialkylphenylsilane of the formula R^(a)R^(b) ₂SiCH₂X′(wherein R^(a) and R^(b) are as described above for Process A, and X′ isCl, Br, or I) and magnesium, in the presence of copper (I) salt such asCu (I) bromide dimethylsulfide complex. In one embodiment,(chloromethyl)dimethylphenylsilane is used to prepare the Grignardreagent. A trimethylsilylating reagent such as chlorotrimethylsilane(TMSCl) can be used to treat the intermediate enolate to form the silylenol ether of formula 34. The resulting silyl enol ether ishydroxymethylated, for example by using aqueous formaldehyde in thepresence of a Lewis acid, e.g., Yb(OTf)₃, La(OTf)₃, Pr(OTf)₃, Nd(OTf)₃,Sm(OTf)₃, Eu(OTf)₃, Eu(OTf)₃, Gd(OTf)₃, Dy(OTf)₃, Ho(OTf)₃, or Er(OTf)₃in THF to give the compound of formula 35.

The compound of formula 35 can be dehydrated by reacting the compoundwith a sulfonylating agent of the formula R³SO₂Cl, wherein R³ is C₁ toC₆ alkyl, trifluoromethyl, phenyl, or substituted phenyl (substituted byC₁ to C₆ alkyl and/or C, to C₆ alkoxy) in the presence of a tertiaryamine base, e.g., triethylamine, and then eliminating the intermediatesulfonate by addition of a strong base, preferably DBU, to give themethylene compound of formula 36. Preferably the sulfonylating agentused is methanesulfonyl chloride. The carbonyl moiety of the methylenecompound of formula 36 can be reduced by hydride reagents thatselectively effect 1,2-reduction of the carbonyl group and provides theallylic alcohol with high diastereoselectivity. These hydride reagentsinclude sodium borohydride, zinc borohydride, lithium aluminum hydride,diisobutylaluminum hydride, sodium borohydride-cerium chloride, lithiumtriethylborohydride, lithium 9-BBN hydride, 9-BBN pyridine,borane-sulfide complex,5,5-diphenyl-2-methyl-3,4-propan-1,3,2-oxazaborolidine (Corey Reagent),lithium tri-tert-butoxyaluminum hydride, sodium cyanoborohydride,lithium tri-sec-butyl borohydride (L-Selectride®), sodiumbis(2-methoxyethoxy)aluminum hydride (Red-Al®), diisobutylaluminumchloride and borane-tetrahydrofuran complex. The carbonyl group can bereduced, for example, with lithium triethylborohydride in THF to givethe crude allylic alcohol of formula 37 in 95% yield in an 8:1diastereomeric ratio. The crude product is purified, for example, usingsilica gel chromatography to isolate the desired diastereomer of theallylic alcohol of the formula 37.

The allylic alcohol of formula 37 is condensed with 2-amino-6-iodopurine(purine compound of formula 28, wherein X is I) under Mitsonobuconditions. Alternatively, other guanine precursors, such as2-amino-6-chloropurine and 2-amino-6-O-benzyloxypurine can be used inthe condensation. Preferred Mitsonobu conditions include treatment ofthe allylic alcohol with about 1.3 molar equivalents each oftriphenylphosphine, DEAD, and 2-amino-6-iodopurine in THF. The productof the Mitsonobu reaction, the methylene compound of formula 38, can befurther purified by, for example, silica gel chromatography.

The methylene compound of formula 38 can be converted to the compound offormula 21. In one conversion method, the dialkylphenylsilane moiety ofthe methylene compound of formula 38 can be converted to a hydroxymoiety by oxidation procedures analogous to those used in Processes Band C. The silyl ether protecting group is simultaneously hydrolyzedduring these procedures. For example, the methylene compound of formula38 can be treated with tetrafluoroboric acid-dimethyl ether complex inDCM. After addition of potassium bicarbonate and potassium fluoride, theintermediate silanol from this reaction is oxidized with hydrogenperoxide to provide the compound of formula 39. The two reactions can beconveniently performed using a one-pot procedure. The 6-iodo group canbe hydrolyzed by heating the compound of formula 39 with aqueous basesuch as a 2 N sodium hydroxide solution. After neutralization theaqueous solution can be heated with decolorizing carbon and allowed tocrystallize to furnish the purified compound of formula 21.

Process G includes preparation of a cyclopentane epoxide of the formula45, and coupling of the cyclopentane epoxide with a guanine precursor togive a carbocyclic nucleoside, the compound of formula 46. The compoundof formula 46 can then be converted by a series of synthetic steps tothe compound of formula 21. One embodiment of Process G is depicted inScheme 14.

In Process G, the cyclopentenone of formula 33 (prepared as described inProcess F) can be iodinated, for example, by treatment with iodinesolution. Preferably, the reaction solvent is a mixture of DCM andpyridine. The resulting iodo cyclopentenone intermediate is reduced,with a hydride reagent, for example, sodium borohydride in MeOH, to formthe iodo compound of formula 40 in >98% de The iodo compound of formula40 can then be subjected to a carbonyl insertion reaction. For example,the allylic alcohol of formula 40 is reacted with carbon monoxide and analcohol ROH wherein R is C₁ to C₄ alkyl or benzyl to form the ester offormula 41. Preferably, the insertion reaction is conducted with carbonmonoxide and MeOH in the presence of a tertiary amine base, e.g.,triethylamine, in a pressurized sealed reaction vessel. The reaction ispreferably catalyzed by a palladium catalyst, e.g., dichlorobis(triphenylphosphine)palladium. The crude product from the insertionreaction can be purified by column chromatography to provide purecompound of formula 41.

The secondary alcohol of the compound of formula 41 is acylated bytreatment with an activated acid derivative of the formula R²C(O)—Y, anda base, preferably lithium hexamethyldisilazide. While other activatedacid derivatives can be used (including alkyl and aryl acid derivatives)to form the acyl intermediate 42, adamantane carbonyl chloride ispreferably used (i.e., R²=adamantane). With this preferred reagent, amore crystalline intermediate is obtained that is more easily purifiedand handled. The intermediate of formula 42 is subjected to allylicdisplacement by treatment with the Grignard reagent prepared from a(halomethyl)dialkylphenylsilane of the formula R^(a)R^(b) ₂SiCH₂X′(wherein R^(a) and R^(b) are as described above for Process A, and X′ isCl, Br, or I) and magnesium, in the presence of copper (I) salt such asCu (I) iodide. In one embodiment, (chloromethyl)dimethylphenylsilane isused to prepare the Grignard reagent. The reaction product, the compoundof formula 43, can be used in the next synthetic step without furtherpurification.

The compound of formula 43 can be reduced with a hydride reagent, suchas diisobutylaluminum hydride in toluene, to provide the allylic alcoholof formula 44. Epoxidation of the crude allylic alcohol of the formula44 provides the cyclopentane epoxide having the formula 45. For example,in one epoxidation method, the allylic alcohol is treated with aperacid, e.g., magnesium monoperoxyphthalate (MPPA) in MeOH, to preparethe cyclopentane epoxide. Using this method, the cyclopentane epoxide offormula 45 is of sufficient diastereomeric purity to be used in the nextsynthetic step without further purification.

In the next step of Process G, the cyclopentane epoxide of formula 45 isconverted to the compound of formula 46 by condensation with an alkalimetal salt, e.g. lithium salt, of 2-amino-6-O-benzyloxypurine in adipolar aprotic solvent, e.g., DMF. The lithium salt, for example, canbe generated by reaction of 2-amino-6-benzyloxypurine with lithiumhydride. The crude product from the condensation reaction can bepurified by recrystallization from a suitable solvent, e.g., MeOH, toprovide the pure compound of formula 46. Here again similar to ProcessesB and C, alkali metal salts of other guanine precursors, e.g.,2-amino-6-chloropurine, 2-amino-6-iodopurine, can be used in place of2-amino-6-benzyloxypurine to couple with the cyclopentane epoxide of theformula 45.

The diol moiety of the compound of formula 46 is then converted to analkene. For example, the conversion to the methylene compound of formula47 can be performed using a two step procedure. The compound of formula46 is treated with an orthoformate derivative, preferablytrimethylorthoformate, and a catalytic amount of an acid such as TFA orPTSA, or acid catalyst such as PPTS. The excess orthoformate reagent isevaporated, and the resulting mixture of dioxolanes is heated withacetic anhydride. The methylene compound of formula 47 is obtained afterevaporation of the acetic anhydride and acid workup, which treatmentalso hydrolyzes the 6-O-benzyloxy group. In embodiments of Process G,wherein X is Cl or I, the 6-halo group on the purine can be hydrolyzedusing hydroxide solution, e.g., NaOH.

The phenyldimethylsilylmethyl group of the methylene compound of formula47 can be converted to a hydroxymethyl moiety, for example, by theprocedures described in Processes B, C, and F. For example, in oneembodiment, the methylene compound of formula 47 can be treated withtetrafluoroboric acid-dimethyl ether complex in DCM to provide thesilanol intermediate. Treatment of the silanol intermediate withpotassium bicarbonate, potassium fluoride, and hydrogen peroxideprovides the compound of formula 21.

In Process H of the invention, a bicyclic lactone, the compound offormula 52, is converted to a methylene compound of formula 56. Themethylene compound of formula 56 is coupled with a guanine precursorsuch as 2-amino-6-chloropurine (purine compound of formula 28, X=Cl) togive a carbocyclic nucleoside, the methylene compound of formula 57. Themethylene compound of formula 57 is subsequently converted to thecompound of formula 21 by deprotection and hydrolysis steps. Embodimentsof Process H are depicted in Scheme 15.

The compound of formula 52 can be treated with the oxaziridine reagent,e.g., (1S)-(+)-(10-Camphorsulfonyl)oxaziridine, and a strongnon-nucleophilic base, preferably sodium bis[trimethylsilyl]amide(NaHMDS) in THF, to generate a compound of formula 53. After quenchingthe reaction with, for example, MeOH, the compound of formula 53 can bedirectly reduced by treatment with a suitable hydride reagent such assodium borohydride in MeOH, to reduce the lactone moiety and provide thecompound of formula 53A. The vicinal diol of the compound of formula 53Acan be oxidatively cleaved by treatment with an oxidizing agent such assodium periodate, potassium permanganate, or ruthenium oxide. Theresulting aldehyde containing intermediate 53B can then be reduced witha suitable hydride reagent, e.g., sodium borohydride, to generate thediol of the formula 54.

The primary alcohol moiety of the diol of formula 54 can be selectivelyconverted to a suitable leaving group, preferably using a sulfonylatingreagent having the formula R³SO₂Cl, wherein R³ is C₁ to C₆ alkyl,trifluoromethyl, phenyl, or substituted phenyl (substituted by C₁ to C₆alkyl or C₁ to C₆ alkoxy). For example, the diol of formula 54 istreated with p-toluenesulfonyl chloride (TsCl), a tertiary amine basesuch as pyridine, and a catalytic amount of 4-N,N-dimethylaminopyridineto convert the primary alcohol to a tosylate group. The secondaryalcohol is protected as an ester by acylation with an acylating agent toprovide the compound of formula 55. Preferably the secondary alcohol isprotected by an acyl group of the formula R²C(═O)—, wherein R² is alkyl,aryl, arylalkyl, any of which can be substituted. Most preferably, R² ismethyl so that the acyl protecting group in the compound of formula 55is acetyl. A preferred acylating agent is an acylating agent of theformula R²C(O)Y, wherein Y is a leaving group. For example, theacylating agent can be an anhydride, acid chloride, and the like.

The compound of formula 55 is treated with an iodide salt, e.g., lithiumiodide, and a strong base such as DBU to effect elimination of theintermediate iodide. Hydrolysis of the acyl ester is carried out bydirect addition of MeOH to the basic reaction mixture, providing themethylene compound of formula 56. The methylene compound of formula 56can be further purified by, for example, silica gel chromatography.

The methylene compound of formula 56 serves as a suitable compound forcoupling with a guanine precursor (purine compound of formula 28,wherein X is Cl, Br or benzyloxy). For instance, the methylene compoundof formula 56 is treated under Mitsonobu conditions with2-amino-6-chloropurine to give the methylene compound of formula 57.Preferably the Mitsonobu conditions comprise treatment with DEAD andtriphenylphosphine. The methylene compound of formula 57 can be furtherpurified by, for example, silica gel chromatography.

The conversion of the methylene compound of formula 57 to the compoundof formula 21 can be completed by deprotection of the silyl ethermoieties and hydrolysis of the 6-X group on the purine moiety. The twosilyl ether moieties are cleaved by treatment with fluoride ion (e.g.,tetralkylammonium fluoride reagent such as tetrabutylammonium fluoridein THF) to give the compound of formula 39. In embodiments of theprocess wherein the purine moiety has a 6-chloro or iodo group, the6-halo group is hydrolyzed by heating the compound of formula 39 withaqueous base or acid, preferably aqueous base, e.g., 2 N sodiumhydroxide solution, to give the compound of formula 21. In embodimentsof the process where X is a 6-O-benzyloxy group, conversion to the 6-oxogroup can be performed using acidic conditions, e.g. 2 N HCl. Thecompound of formula 21 can be further purified by, for example, silicagel chromatography.

In Process H, the homochiral bicyclic lactone of formula 49 can be usedas starting material for the preparation of the compound of formula 52,and can be prepared as described in Corey et al. J. Med. Chem. 1993, 36,243. The bicyclic lactone of formula 49 can be treated withparaformaldehyde in a mixture of glacial acetic acid and sulfuric acidto add formaldehyde across the double bond. This treatment yields adiacetate of formula 50. The diacetate of formula 50 is subsequentlystirred with a base such as potassium carbonate in an alcohol solvent,e.g., MeOH, to hydrolyze the acetate moieties and provide the diol ofthe formula 51. The alcohol moieties of the diol of formula 51 can beprotected as silyl ether groups by treating the diol with a silylatingreagent of the formula R^(c)R^(d) ₂SiY (wherein R^(c), R^(d) and Y areas described above in the description of Process E) to provide thecompound of formula 52. In one embodiment of Process H, the silylatingreagent is tert-butyldimethyl chloride (TBSCl).

Similar to Process H of the invention, Process I of the inventioncomprises preparation of a methylene compound of formula 56 from thehomochiral bicyclic lactone intermediate, the compound of formula 52.The coupling of the methylene compound of formula 56 to a guanineprecursor (purine compound of formula 28), and subsequent conversion ofthe resultant carbocyclic nucleoside to the compound of formula 21 areanalogous to the methods used in Process H as well. The preparation ofthe methylene compound of formula 56 from the compound of formula 52,however, is achieved by different synthetic methods than those used inProcess H. One embodiment of Process I is depicted in Scheme 16.

In Process I, the lactone moiety of the compound of formula 52 isreduced under controlled reaction conditions to provide the lactol offormula 59. For instance, the compound of formula 52 can be treated witha hydride reagent, e.g., diisobutylaluminum hydride in toluene at 25° C.to achieve reduction to the lactol oxidation state. The reductionproduct, the lactol of formula 59, is subsequently cleaved using anoxidizing agent, such as iodobenzene diacetate under UV irradiation (sunlamp) in DCM to give the iodide compound of formula 60. The iodidecompound of formula 60 can be treated with a strong base such as DBU toeffect elimination of the iodide moiety with removal of the formateester upon water workup to yield the methylene compound of formula 56.

The methylene compound of formula 56 can be coupled to a guanineprecursor, such as 2-amino-6-iodopurine (purine compound of formula 28wherein X is I), under reaction conditions such as those described forthe conversion of the methylene compound of formula 56 to the compoundof formula 57 described above in Process H. The resulting carbocyclicnucleoside, the compound of formula 39, can be converted to the compoundof formula 21 by methods such as those used in the Process H.

Process J of the invention depicts another approach for the preparationof the compound of formula 21 (Scheme 17). Process J includes formationof a methylene compound of formula 89, and subsequent coupling of themethylene compound with a guanine precursor, e.g., 2-amino-6-iodopurine,using Mitsonobu conditions to yield a carbocyclic nucleosideintermediate, the methylene compound of formula 90. The protectinggroups of 90 are removed and the X group is hydrolyzed to provide thecompound of formula 21.

The methylene compound of formula 89 is prepared from the cyclopentaneepoxide of formula 82, prepared as described in Example 1 of U.S. Pat.No. 5,206,244. The secondary alcohol moiety of 82 is protected as asilyl ether having the formula R^(c)R^(d) ₂SiO— wherein R^(c) and R^(d)are as described above in the description of Process E. In oneembodiment, the secondary alcohol of 82 is protected as a tert-butyldimethylsilyl ether. The primary alcohol is unmasked by catalyticreduction of the benzyl group of 83 with, for example, palladium oncarbon to give the compound of formula 84. The compound of formula 86 isprepared by a base catalyzed elimination procedure. In the first step ofthe procedure, the primary alcohol of 84 is converted into a suitableleaving group, preferably using a sulfonating reagent having the formulaR³SO₂Cl, wherein R³ is as described above in Process F, to give thecompound having the formula 85. A strong base, e.g., potassiumt-butoxide, in a suitable solvent, e.g. THF, is then used to effect theelimination of alkyl or (substituted) phenylsulfonic acid to provide theexocyclic methylene moiety in the compound of formula 86.

A hydroxymethyl moiety is then installed on the cyclopentane ringadjacent to the exocyclic methylene moiety in the compound of formula 86to give the compound of formula 87. To efficiently effect thistransformation, a regioselective 1,2-addition of a carbon nucleophile tothe epoxide of the compound of formula 86 is preferably conducted.Preferably, the carbon nucleophile is a carbanion of 1,3-dithiane, e.g.,lithium salt of 1,3-dithiane, that adds to the allylic position toprovide the compound of formula 87. The lithium salt of 1,3-dithiane canbe generated with a strong non-nucleophilic base, e.g., n-butyl lithium,lithium diisopropylamide, lithium hexamethylsilazide, and the like in anethereal solvent, e.g., THF. A chelating agent such as1,4-diazabicyclo[2.2.2]octane (DABCO) is preferably added to enhance theefficiency of the process. The reaction is preferably carried out below25° C., more preferably below about −15° C. to ensure highregioselectivity. Preferably, the regioselectivity of the additionis >10:1, more preferably >15:1.

The dithianylmethyl group of the compound of formula 87 is readilyconverted to an alcohol by a hydrolysis reaction followed by a reductionreaction. The hydrolysis to an intermediate aldehyde is carried out, forexample, by stirring a mixture of compound of formula 87 with calciumcarbonate and iodomethane in aqueous acetonitrile. Other methods forhydrolyzing dithioacetals are well known in the art and include methodsrecited in Greene, T. W.; Wuts, P. G. M. Protecting Groups in OrganicSynthesis 2nd Edition; Wiley and Sons: New York, 1991, pp. 199-201. Theintermediate aldehyde can be reduced with a suitable hydride reagent,e.g., sodium borohydride, to provide the compound of formula 88.

The compound of formula 88 is converted to a compound suitable forcoupling with a protected guanine derivative, by acylation of thealcohol groups. Acyl groups of the formula R²C(═O)— wherein R² is asdescribed above for Process H can serve as protecting groups.Preferably, R² is methyl so that the acyl group is acetyl. The silylether group is then cleaved using fluoride ion, e.g., tetrabutylammoniumfluoride, to give the methylene compound of formula 89.

The compound of formula 89 is coupled to a suitable guanine precursor,e.g., 2-amino-6-iodopurine, to provide a carbocyclic nucleosideintermediate, the methylene compound of formula 90. In alternativeembodiments, 2-amino-6-chloropurine or 2-amino-6-benzyloxypurine can beused as the guanine precursor.

The methylene compound of formula 90, can be converted to the compoundof formula 21 by suitable hydrolysis methods. For example, the estergroups can be cleaved by treatment with an alkali metal alkoxide, e.g.sodium methoxide, and the 6-halo group can be hydrolyzed by heating inaqueous base. In embodiments of the process wherein2-amino-benzyloxypurine is used as a guanine precursor, the 6-benzyloxygroup is hydrolyzed using acid, e.g., HCl.

Process K Resin Purification

Another aspect of this invention is the use of a resin adsorptionprocess for isolation and purification of the compound of formula 21 orintermediates thereof. This process employs a crude mixture comprisingcompound 21 or a mixture comprising entacavir intermediate(s) and otherreagents, such as, for example, an oxidative mixture resulting from thetreatment of an intermediate for compound 21 with hydrogen peroxide inan oxidative desilylation reaction in the presence of KF and KHCO₃.Compound 21 is soluble in water at 2.2 mg/mL and more preferably below1.5 mg/mL. Compound 21 and related compounds are adsorbed on the resinspecifically while inorganic salts pass through. The resin bed is thenwashed with water to remove any additional salts and compound 21 or acompound related thereto (e.g., such as an intermediate or precursor) iseluted from the resin via washing with an organic solvent. In oneembodiment, the organic solvent comprises a mixture of MeOH and water,preferably 40-60% MeOH:40-60% water, more preferably 45-55% MeOH:45-55%water, even more preferably 50:50 MeOH and water, as 50% MeOH providesoptimal separation of compound 21 or compound related thereto which isthen concentrated and crystallized to obtain a pure compound. As useherein, by “pure” it is meant a compound having greater than or equal to97%, or more preferably 99%, purity. Most preferred is a compoundwherein all impurity peaks are less than 0.1 area percent as determinedby high performance liquid chromatography (HPLC).

Resins suitable for use in this adsorption process are hydrophobicresins with selectivity for non-polar molecules. In one embodiment, theresin is styrene-based. More preferably, the styrene-based resins arebrominated to provide for greater strength and abrasion resistance.Exemplary resins with such properties include, but are not limited to,SP207 Sepabeads, SP700 Sepabeads, Diaion HP20, Diaion SP70, DiaionSP825, Diaion SP850, Diaion HP2MG methacrylate, AMBERLITE XAD4,AMBERLITE XAD7HP, AMBERLITE XAD16, and AMBERLITE XAD1600. In a preferredembodiment, SP207 is used as the resin as this resin exhibits abrasionresistance, long-term recycling utilization, and the ability towithstand extremes of organic solvent conditions, temperatures, and pH,to be particularly useful in purification of compound 21 and compoundsrelated thereto.

The following examples further illustrate the present invention, but ofcourse, should not be construed as in any way limiting its scope.

EXAMPLE 1 PROCESS FOR THE PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one(21) PREPARATION OF (1α,4α,5α)-7,7-Dichloro-4-(dimethylphenylsilyl)bicyclo[3.2.0]hept-2-en-6-one (63)

A 3-L three necked flask equipped with a mechanical stirrer, a 500-mLaddition funnel, a thermometer and an argon inlet was charged withphenyldimethylchlorosilane (153.6 g, 0.90 moles) and anhydrous THF (320mL). The flask was then cooled to −78° C. To this stirring solution, wasadded sodium cyclopentadienide (441 mL, 2.04 M in THF, 0.90 moles) overa period of one hour. The reaction mixture was stirred for about twohours and then it was allowed to warm to about 0° C. over a period oftwo hours. At this time the reaction was assumed to be complete. Thereaction was quenched by addition of cold water (˜150 mL) and allowed towarm to ˜15° C. The mixture was diluted with hexanes (˜100 mL) andtransferred to a separatory funnel. The organic layer was separated andthe aqueous layer was extracted with hexanes (200 mL). The combinedorganic layer was washed with brine (200 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo to give the crudediene as dark brown oil (177 g, ˜98% yield). The crude diene was usedwithout further purification in the next reaction.

A 3-L three necked flask equipped with a mechanical stirrer, 500-mLaddition funnel, thermometer, and argon inlet was charged with diene ofthe above reaction (176.5 g, 0.88 moles) and hexanes (600 mL). Themixture was cooled to about −10° C. and dichloroacetyl chloride (173 mL,1.80 moles) was added over the course of five minutes. To this stirredmixture a solution of Et₃N (251 mL, 1.80 moles) in hexanes (400 mL) wasadded over a period of one hour. The resulting mixture was stirred forabout three hours at 0-4° C. and then at ambient temperature for aboutten hours to complete the reaction. The reaction was quenched byaddition of water (400 mL). After stirring for about 30 minutes at roomtemperature, the solution was transferred to a separatory funnel and theorganic layer was separated. The aqueous layer was extracted withhexanes (300 mL). The combined organic layer was washed with water (250mL), sodium bicarbonate (5%, 250 mL) and water (500 mL). The combinedfiltrate was concentrated in vacuo. The resulting dark oil was furtherdried under high vacuum to give 307 g of the crude title compound.

PREPARATION OFtrans-5-(Dimethylphenylsilyl)-2-(hydroxymethyl)-2-cyclopentene-1-carboxylicacid (64)

A 3-L three necked flask equipped with a mechanical stirrer, a 500-mLaddition funnel, a thermometer and an argon inlet was charged with theabove obtained 63 (211 g, 0.68 moles), tert-butanol (348 g), water (710mL), and Et₃N (343 g, 3.39 moles). The reaction mixture was heated toreflux for 3 hours. The reaction mixture was cooled to ˜10° C. andpotassium carbonate (300 g, 2.17 moles) was added over 30 minutes. After30 minutes, sodium borohydride (13.6 g, 0.359 moles) was added inportion-wise. After 1 hour the cooling bath was removed and the reactionmixture was allowed to warm slowly. The reaction mixture was carefullyquenched with water (800 mL). The pH was adjusted to ˜3.0 and theresulting mixture extracted with EtOAc (800 mL). The organic extract wasconcentrated in vacuo. The resulting dark oil was further dried underhigh vacuum give 185 g of the racemic title compound.

PREPARATION OF(1R,5S)-5-(Dimethylphenylsilyl)-2-(hydroxymethyl)-2-cyclopentene-1-carboxylicacid, (1R,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (1:1) salt (65A)

A 3-L three necked flask equipped with a mechanical stirrer, additionfunnel, thermometer and argon inlet was charged with 64 (185 g, 0.67moles), absolute ethanol (925 g) andR,R-(−)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (102 g, 0.483 moles),and heated to 50° C. The solution was seeded with the salt 65A and leftat 40° C. for 5 hours. The resulting crystals were filtered on a Buchnerfunnel and washed with ethanol. The solid was dried to give the titlecompound in ˜28.3% yield (94 g) from sodium cyclopentadienide. Theproduct has a purity of 98 AP and 99% ee.

PREPARATION OF(1R,5S)-5-(Dimethylphenylsilyl)-2-(hydroxymethyl)-2-cyclopentene-1-carboxylicacid methyl ester (66)

To a 2-L 3-necked round bottomed flask equipped with a mechanicalstirrer, an addition funnel and a thermometer, was charged 65A (390 g,0.8 mole) and MeOH (800 mL). The reaction mixture was cooled to about 0°C. Concentrated sulfuric acid (123 g, 1.2 moles) was slowly added to thereaction flask with stirring. After addition of the acid, the reactionmixture was stirred for about 12 hours at room temperature to completethe reaction. After completion of the reaction, the reaction mixture wasconcentrated in vacuo to remove about 500 mL of MeOH. The residue wasdiluted with EtOAc (600 mL) and water (1000 mL). The mixture wastransferred to a separatory funnel and the organic layer was separated.The aqueous layer was extracted with EtOAc (600 mL). The combinedorganic layer was washed with saturated sodium bicarbonate (500 mL),water (500 mL), brine (500 mL) and concentrated in vacuo to afford thecrude title compound (224 g) as a brown oil.

PREPARATION OF[1R-(1α,2α,3β,5α)]-3-(Dimethylphenylsilyl)-6-oxabicyclo[3.1.0]hexane-1,2-dimethanol(72)

To a 5-L 3-necked round bottomed flask equipped with a mechanicalstirrer, an addition funnel and a thermometer, was charged activatedmolecular sieves (224 g) and DCM (1000 mL) under an atmosphere of argon.The solution was cooled to about −30° C. DIPT (18 g, 0.08 moles) wasadded to the solution and the mixture stirred at −30° C. for about 20minutes. Titanium (IV) isopropoxide (18.2 mL, 0.064 moles) was thenadded to the reaction mixture. The reaction mixture was stirred at −30°C. for about 20 minutes.

Compound 66 (224 g, 0.8 moles) in DCM (500 mL) was charged to thereaction mixture via syringe at −30° C. The reaction mixture was stirredat −30° C. for about 20 minutes. TBHP (308 mL, 5 M/decane, 1.6 moles)was added to the reaction mixture using an addition funnel, keeping thereaction temperature between −20° C. to −30° C. After complete additionof TBHP, the reaction mixture was stirred between −20° C. to −30° C. forabout 2 hours. After the reaction was complete, the excess peroxide wasquenched by addition of aqueous sodium bisulfite (250 g of sodiumbisulfite in 500 mL of water). After the addition of sodium bisulfite,the mixture was stirred for about 30 minutes and filtered through a padof diatomaceous earth (CeliteHyflo®). The filtrate was transferred to aseparatory funnel and the aqueous layer was separated. The organic layerwas washed with saturated sodium bicarbonate solution (1000 mL) and thenwater (500 mL). The organic layer was concentrated in vacuo to give thecrude epoxide (276 g) as an oil.

To a 3-L 3-necked round bottomed flask equipped with a mechanicalstirrer and a thermometer was charged the above obtained epoxide (276 g,0.8 moles) and IPA (800 mL) under an atmosphere of argon. The resultingsolution was cooled to about 0° C. in an ice bath and to it was addedsolid sodium borohydride (68 g, 1.6 moles) in portions. After theaddition was complete, the cooling bath was removed and the reactionmixture was stirred for about 16 hours to complete the reaction. Aftercompletion of the reaction, the excess borohydride was quenched byadding the reaction mixture to a solution of saturated ammonium chloride(2000 mL). After the borohydride was completely quenched, the reactionmixture was extracted with EtOAc (1200 mL). The organic layer was washedwith water (500 mL), brine (500 mL), and concentrated in vacuo to affordthe title compound (251 g) as light yellow oil.

PREPARATION OF [1S-(1α,2β,3α,4β)]-1-[2-Amino-6-(phenylmethoxy)-9H-purin-9-yl]-4-(dimethylphenylsilyl)-2-hydroxy-2,3-cyclopentanedimethanol(73, X=BnO)

To a 3-L 3-necked round bottomed flask equipped with a mechanicalstirrer and a thermometer, was charged 2-amino-6-benzyloxypurine (193 g,0.8 moles), lithium hydroxide monohydrate (33.6 g, 0.64 moles) and 72(251 g, 0.8 moles) in DMF (800 mL). The mixture was heated to 80° C. andstirred for about 20 hours. After completion of the reaction, thereaction mixture was cooled to room temperature and extracted with EtOAc(3000 mL). The organic layer was washed with brine (1500 mL). Theorganic layer was washed with citric acid (1000 mL), brine (1000 mL) andconcentrated in vacuo to furnish crude triol (330 g) as a thick brownoil. The product was crystallized from EtOAc-hexanes to give the titlecompound (˜225 g) as a solid crystalline material.

PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-9-[4-(dimethylphenylsilyl)-3-(hydroxymethyl)-2-methylenecyclopentyl]-1,9-dihydro-6H-purin-6-one(71)

A 2.0-L 3-necked round bottomed flask, oven dried and equipped with amechanical stirrer, an addition funnel, a temperature probe, and argoninlet, was charged with 73 (77.5 g, 0.1493 moles), pyridiniump-toluenesulfonate (1.875 g, 0.007465 mole), and DCM (371 mL) under anargon atmosphere. The resulting slurry was stirred and cooled to 0° C.Diethoxymethyl acetate (122 mL, 0.7465 moles) was added slowly over aperiod of about 15 minutes. The reaction mixture was warmed to roomtemperature over a period of one hour. After the complete consumption ofthe starting material, the resulting brown reaction mixture was slowlyadded to a stirring saturated solution of sodium bicarbonate (775 mL).The resulting mixture was extracted with EtOAc (1000 mL). The organiclayer was concentrated in vacuo to afford a mixture of dioxolanes as aviscous brown oil (˜125 g) which was transferred to a 2-L 3-necked roundbottomed flask. The flask was additionally charged with acetic anhydride(279 mL, 2.96 moles) and heated at about 120° C. for 30 hours. After thecomplete consumption of the starting material, the reaction mixture wascooled ˜65° C., and MeOH (745 mL) was added. The reaction mixture wasstirred while maintaining the temperature at 65° C. for 40 minutes.Water (5-10 mL) was added to the reaction mixture, and the reactionmixture was cooled to about 45° C. Concentrated HCl (220 mL) was addedand the mixture was reheated at 65° C. for 4 hours. The mixture wascooled to ˜20° C., and extracted with a hexane-tert-butyl methyl ether(9:1) mixture (1500 mL). The organic extract was concentrated in vacuo.The residue was transferred to a 3-L 3-necked flask and heated to 55° C.and at this temperature, 10 N NaOH (413 mL) was added to adjust the pHof the solution to about 12.8. The reaction mixture was heated to 75° C.and stirred at that temperature for ˜4 hours. Concentrated HCl (30 mL)was slowly added to the reaction mixture to adjust the pH to 7 and thereaction mixture was allowed to cool to 20° C. over a 4 hour period. Theslurry was filtered and the cake washed with a mixture of coldMeOH-water (3:7) (200 mL), followed by water (800 mL), and tert-butylmethyl ether (150 mL). The light brown colored crude product was driedto afford the title compound (37.7 g, 64%).

PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one(21)

A 2-L 3-necked round bottomed flask, oven dried and equipped with amechanical stirrer, an addition funnel, temperature probe, and argoninlet, was charged with compound 71 (34.1 g, 86.2 moles), acetic acid(40.4 mL, 8 eq) and acetic acid-boron trifluoride complex (38 mL). Thereaction mixture was heated to 95° C., stirred for 4 hours and thencooled to room temperature. The reaction mixture was diluted with MeOH(200 mL) and quenched with aqueous KOH (10 N, ˜220 mL) to adjust the pHto about 9.5. Potassium bicarbonate (17.9 g) followed by aqueoushydrogen peroxide (30 wt. %, 39 g) was added to the solution. Theresulting solution was warmed to 70° C. and stirred for 10 hours. Thereaction was cooled to 5-10° C. Sodium bisulfite (16.2 g) was addedportion-wise over 30 minutes. The reaction mixture was concentrated invacuo to remove most of the MeOH. The resulting yellow semi-solid wascooled to −5° C. and concentrated HCl (˜55 mL) added to adjust the pH to0.15. The resulting solution was extracted with EtOAc (500 mL) andaqueous KOH (10 N, ˜48 mL) added to adjust the pH to ˜11. The solutionwas stirred for 1 hour and then the pH was adjusted to ˜7 with HCl (4mL). The reaction mixture was stirred at room temperature for 1 hour andat ˜5° C. for 3 hours. The solid was collected by filtration and driedunder high vacuum for 16 hours. The solid was redissolved in water (600mL) at 90° C. The clear solution was cooled to ˜60-55° C. and seededwith 21. The solution was allowed to cool to room temperature for 5hours. The resulting white crystalline solid was collected by filtrationand dried under vacuum at 50° C. for 16 hours to afford the titlecompound (12.9 g).

EXAMPLE 2 PROCESS FOR THE PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one(21) PREPARATION OF(1R,5S)-5-(Dimethylphenylsilyl)-2-[(1-methoxy-1-methylethoxy)methyl]-2-cyclopentene-1-methanol(75)

To a 1-L 3-necked round bottomed flask equipped with a mechanicalstirrer and a thermometer was charged 66 (29.6 g, 0.1 moles, obtained asdescribed in Example 1) and toluene (50 mL) under an atmosphere ofargon. The resulting solution was cooled to ˜0° C. in an ice bath and2-methoxypropene (95 mL, 1.0 mole) was added. Pyridiniump-toluenesulfonate (0.5 g, 0.002 moles) was added at 0° C. and theresulting mixture was stirred at 0° C. for 10 minutes. The cooling bathwas removed and the reaction mixture was stirred at room temperature for1.5 hours. After completion of the reaction, the reaction mixture wascooled to −78° C. Triethylamine (27 mL, 0.2 moles) was added to keep thereaction mixture in a basic environment. LAH (1 M in THF, 0.1 moles) wasadded at −78° C. The cooling bath was removed after 30 minutes and thereaction was allowed to warm to ambient temperature. The reactionmixture was stirred at room temperature for 1-2 hours. The reactionmixture was cooled to 0° C. and 2 N NaOH (20 mL) was added. After thisaddition, the reaction mixture was stirred for 30 min and filtered. Thepad was washed with DCM (400 mL). The organic filtrate was washed withbrine (100 mL) and concentrated in vacuo to afford the title compound(35 g) as a light yellow oil.

PREPARATION OF(4S,5R)-4-(Dimethylphenylsilyl)-5-[(phenylmethoxy)methyl]-1-cyclopentene-1-methanol(76)

To a 250-mL 3-necked round bottomed flask equipped with a mechanicalstirrer and a thermometer was charged 75 (35 g, 0.1 moles) and THF (60mL) under an atmosphere of argon. NaH (6 g, 60%, mineral oil suspension,0.15 moles) was added to the solution. The mixture was heated at 60° C.for 1 hour and then cooled to room temperature. Benzyl bromide (23.8 mL,0.2 moles) and tetrabutylammonium bromide (10 g, 0.03 moles) were addedto the suspension. The reaction mixture was heated at 70° C. for 6 hoursand then the reaction mixture was cooled to room temperature.1,9-diazabicyclo[5.4.0]undecen-7-ene (45 mL, 0.2 moles) was added andheated at 50° C. for 45 min. The reaction mixture was cooled to roomtemperature, quenched with 1N HCl to pH ˜1 and extracted with a mixtureof EtOAc-hexane (250 mL). The organic layer was washed with water (500mL), brine (100 mL) and concentrated in vacuo to afford the titlecompound (42 g) as a brown oil.

PREPARATION OF[1R-(1α,2α,3β,5α)]-3-(Dimethylphenylsilyl)-2-((phenylmethoxy)methyl]-6-oxabicyclo[3.1.0]hexane-1-methanol(77)

To an oven dried, 1-L 3-necked round bottomed flask equipped with amechanical stirrer, a temperature probe, and an argon line was chargedactivated molecular sieves (35 g) and DCM (160 mL) under an atmosphereof argon. The solution was cooled to about −30° C. DIPT (2.34 g, 0.01moles) followed by titanium (IV) isopropoxide (2.36 mL, 0.008 moles) wasadded to the reaction mixture. The reaction mixture was stirred at −30°C. for about 20 minutes. Crude 76 (42 g, ˜0.1 moles) in DCM (40 mL) wasadded to the reaction mixture and stirred for about 30 minutes. TBHP (40mL, 0.2 moles) was added to the reaction mixture at −30° C. Aftercomplete addition of TBHP, the reaction mixture was stirred at −30° C.for about 5 hours to complete the reaction. The excess peroxide wasquenched with aqueous sodium bisulfite (20 g). The mixture was filteredthrough a Buchner Funnel with a pad of diatomaceous earth (HyfloCelite®). The filtrate was washed with saturated NaHCO₃, solution (100mL) and brine (100 mL). The organic layer was concentrated in vacuo togive the crude title compound (60 g, >100% material balance) as an oil.

PREPARATION OF[1R-(1α,2α,3β,5α)]-5-[2-Amino-6-(phenylmethoxy)-9H-purin-9-yl]-3-(dimethylphenylsilyl)-1-hydroxy-2-[(phenylmethoxy)methyl]cyclopentanemethanol(78A, X=BnO)

To a 1-L 3-necked round bottomed flask equipped with a mechanicalstirrer and a thermometer, was charged 2-amino-6-benzyloxypurine (24 g,0.1 moles), lithium hydride (0.48 g, 0.06 moles) and DMF (40 mL). Themixture was heated at 60° C. for about 1 hour under an atmosphere ofargon. 77 (60 g, 0.1 moles) in 20 mL DMF was added. The reactiontemperature was heated at 105° C. for 5 hours, cooled to roomtemperature and diluted with EtOAc (600 mL). The organic layer waswashed with brine (300 mL), 1 M citric acid (150 mL), and NaHCO₃solution (100 mL). The organic layer was concentrated in vacuo tofurnish crude title product (60 g) as an oil. It was crystallized fromEtOAc and hexane to give 23 g of the title compound as a crystallinesolid.

PREPARATION OF[1S-(1α,3α,5β)]-2-Amino-9-[4-(dimethylphenylsilyl)-2-methylene-3-[(phenylmethoxy)methyl]cyclopentyl]-1,9-dihydro-6H-purin-6-one(79)

A 100-mL 3-necked round bottomed flask, oven dried and equipped with amechanical stirrer, an addition funnel, a temperature probe, and anargon inlet was charged with 78A (12.2 g, 0.02 moles), pyridiniump-toluenesulfonate (0.25 g, 0.001 moles) and DCM (20 mL) under argonatmosphere. The resulting solution was stirred at room temperature andDEMA (16 mL, 0.1 moles) was added. The reaction mixture was stirred atroom temperature for one hour. After the complete consumption of thestarting material, the resulting reaction mixture was quenched with asaturated solution of NaHCO₃ (100 mL) and extracted with EtOAc (100 mL).The organic layer was washed with brine (2×50 mL) and concentrated invacuo to afford the mixture of dioxalanes as a viscous oil which wastransferred to a 250-mL 3-necked round bottomed flask, equipped with amechanical stirrer, a condenser, a temperature probe, and an oil bath.Acetic anhydride (20 mL, 0.2 moles) was added to this flask and theresulting mixture was heated at 120° C. for 15 hours. After the completeconsumption of the starting material, the reaction mixture was cooled˜60° C. and MeOH (50 mL) was added. An HCl solution (50 mL, 6 N) wasadded to the reaction mixture and the temperature was raised to 70° C.and stirred for a total of 6 hours. During this period, a 50% MeOH/watersolution was added (50 mL). The reaction mixture was concentrated toremove the excess MeOH (150 mL MeOH) on a rotary evaporator. Theresulting mixture was warmed to ˜50-55° C. NaOH (10 N) was added toadjust the pH of the solution to ∫6.5. The resulting suspension wasstirred at ˜50° C. for 1 hour, and then cooled to 28° C. over the courseof 2 hours. The solid was filtered, washed with 1:2 MeOH/water (80 mL),water (100 mL), and dried to afford the title compound (7.65 g).

Alternative Conversion of 78A to 79

78A (5 kg) was dissolved in toluene (17 L) and treated withpyridium-p-toluenesulfonate (110 g, 0.05 mole) and DEMA (5.33 kg, 4moles) at ambient temperature, affording a diastereomeric mixture oforthoesters. The reaction was quenched with aqueous NaOH whilemaintaining the pH above 7.5. Tert-butyl methyl ether (70 L) was addedand the layers were separated. The product rich organic layer was driedby azetropic distillation to a moisture content of less than 0.1%.Butylated hydroxytoluene (10 kg) and glacial acetic acid (0.99 kg, 2equiv) and acetic anhydride (10.9 kg, 13.2 equiv) were added to thetoluene reaction mixture, and the mixture was heated to 120 to 125° C.for several hours.

At the end of the olefination reaction, the reaction mixture was addedto MeOH (80 L) and aqueous HCl (6 N, 21.6 L) while maintaining thetemperature at less than 35° C. The reaction mixture was heated to 60 to65° C. to effect debenzylation/deacetylation. The reaction mixture wascooled to ambient temperature and washed with heptane (2×35 L) to removebutylated hydroxytoluene. The layers were separated and the product richaqueous methanolic layer was heated to 55 to 65° C. Water (14.2 L) wasadded, followed by cooling to ambient temperature over 2 to 5 hours toeffect crystallization of the hydrochloride salt of 79. The crystalslurry was filtered and washed with water (2×20.2 L) and heptane (2×30L). The filter cake was dried to 60 to 65° C. to a moisture content ofless than 3.5% (3.64 kg, 85.6% yield).

The above hydrochloride salt of 79 (1.26 kg) was suspended in MeOH (13L) and heated to 55 to 65° C. to achieve complete dissolution. Theapparent pH of the solution was adjusted to 5.4 to 6.4 with 1 N NaOH(about 1.5 L) while maintaining the temperature at 50 to 65° C. The freebase slurry was held at 50 to 65° C. for an additional 60 to 90 minutesthen slowly cooled to ambient temperature over 90 to 120 minutes. Morewater (about 1.5 L) was added over 45 to 60 minutes, and the pH wasreadjusted to 5.5 to 6.4 with 1 N HCl or NaOH. The crystal slurry wasfiltered and washed with 1:1 MeOH:water (2.6 L), followed by water (2.8L) and finally heptane (4 L). The cake was dried in a vacuum oven at60-65° C. to a moisture content of less than 1% (1.03 kg, 85%).

The free base can be reprecipitated from toluene/heptane to affordhighly purified 79 in 90-93% yield, 99% AP, 99.0+% potency.

Alternative Conversion of 78A to Methanesulfonate Salt of 79

Under nitrogen, a solution of 78A (50.0 g, 82.06 mmol), triisopropylorthoformate (46.85 g, 246.2 mmol) and TFA (7.02 g, 61.57 mmol) intoluene (300 ml) was stirred for one hour at room temperature. To thissolution were added butylated hydroxytoluene (50 g), acetic anhydride(100 ml) and glacial acetic acid (4.93 g, 82.10 mmol) and the solutionwas heated to 120° C. After holding the reaction solution at 120° C. for12.5 hours, the dark solution was cooled to room temperature and addedto a cold (4° C.) solution of methanesulfonic acid (63.40 g, 659.70mmol) in water (300 ml) at a rate to keep the temperature at 5-10° C.The reaction mixture was stirred for 15 minutes at 5-10° C. and MeOH(600 ml) was added at a rate to keep the temperature at 5-10° C. Afterstirring at 5-10° C. for 15 minutes, the reaction mixture was heated to65° C. and held for 12 hours. After cooling to room temperature, thecrude reaction mixture was washed with heptane (300 ml) and the layersseparated. Additional MeOH (200 ml) was added to the product richaqueous layer, and it was again extracted with heptane (300 ml). Thereaction mixture was heated to 65° C. and water (500 ml) was added so asto keep the temperature at 65-55° C. to initiate crystallization of themethanesulfonate salt. The reaction solution was cooled to 10° C. andthe solids were filtered, washed with water (200 ml), and dried at 50°C. under vacuum to afford 39.5 g of the methanesulfonate salt of 79 withAP of 99.6 and purity of 86.4%.

PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one(21)

To a 500-mL round bottomed flask, equipped with a magnetic stirrer, anitrogen inlet, an oil bath, and a temperature probe was charged 79 (7.2g, 4.7 mmols) and boron trifluoride-acetic acid complex (12.3 mL, 88.2mmols). The reaction mixture was heated at ˜70° C. for 3.5 hours, cooledto room temperature, and diluted with MeOH (80 mL)/H₂O (4 mL). Themixture was neutralized with KOH (10 N, ˜40 mL) to pH ˜9.6. Potassiumbicarbonate (4.45 g, 44.1 mmols) was added to the solution and theresulting suspension was warmed up to ˜60° C. Hydrogen peroxide (30 wt.% in water, 7.49 g, 73 mmols) was added, and then the reaction mixturewas heated at 65° C. for 11 hours. The resulting mixture was cooled to0° C. and sodium bisulfite (4.42 g) was added. MeOH was removed from thereaction mixture. The resulting mixture was diluted with water (50 mL)and acidified with HCl to pH ˜0.5. The mixture was washed with methyltert-butyl ether (100 mL) and neutralized with NaOH (10 N) to pH ˜6.7.The resulting solution was cooled to room temperature and stirred for 6hours to crystallize the product. The white crystalline solid wascollected by filtration to afford 2.05 g of the title compound.

Alternate Conversion of 79 to 21 with Methanesulfonic Salt

A solution of 79 (30 g, 61.77 mmol) in methylene chloride (90 mL) wascooled and treated with methanesulfonic acid (90 mL). The resulting darksolution was stirred at 18-25° C. until the reaction was consideredcomplete by an HPLC analysis. The reaction mixture was then quenchedinto a mixture of 45% aqueous KOH (155 mL) and MeOH (1.8 L) at 10 to 15°C. The resulting potassium methanesulfonate salt that formed was removedby filtration. The filtrate was concentrated, pH adjusted to 7.5 to 8.8with glacial acetic acid (17 mL) and then treated with aqueous KHCO₃(18.6 g in 82 mL of water, 3 equiv), aqueous KF (9.1 g in 25 mL ofwater, 2.5 equiv), and 30% aqueous hydrogen peroxide (19.8 mL, 3.1equiv). The reaction mixture was then held at 60-70° C. until theformation of 21 was complete as determined by HPLC analysis.

Alternate Conversion of 79 to 21 Via Compounds 110 and 114 PREPARATIONOF [1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-(dimethylhydroxylsilyl)-2-methylene-3-[(phenylmethoxymethyl]cyclopentyl]-6H-purin-6-one(110)

An aqueous solution of KOH (45 wt. %, 5.1 mL) was charged to a solutionof compound 79 (4.85 g, 10 mmol) in NMP (49 mL). The mixture was heatedat 50° C. for 12 hours. The reaction was cooled to room temperature.Water (75 mL) was charged while maintaining the reaction temperaturebelow 35° C. The reaction mixture was cooled to 5-10° C., neutralizedwith aqueous HCl (6 N, ˜10 mL) to pH˜7, and then stirred at 0-5° C. for0.5 hour. The solid was collected by filtration, and the wet cake washedwith water (3×50 mL). The solid was dried under vacuum at (50° C.) for24 hours to afford the title compound 110 (3.66 g in 87% yield).

PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-2-methylene-3-[(phenylmethoxymethyl]cyclonentyl]-6H-purin-6-one(114)

A solution of KF (0.14 g, 0.23 mmol) in MeOH (1.4 mL) was added to asuspension of compound 110 (1.0 g, 2.3 mmol) in MeOH (8.4 mL) at roomtemperature. Potassium bicarbonate (0.47 g, 2.3 mmol) was charged to theresulting suspension. The mixture was stirred at 45° C. for 0.5 hour toform a clear solution and aqueous hydrogen peroxide (30 wt. %, 1.6 mL)was added. The reaction was heated at 45° C. for 3 hours, then cooled to0-5° C. An aqueous solution of sodium bisulfite (10 wt. %, 5.0 mL) wasadded portion-wise in 0.5 hour. The mixture was slowly acidified withaqueous HCl (6 N, ˜8 mL) to pH=0.45. The resulting solid was filteredoff and the filtrate neutralized with aqueous NaOH (4 N, ˜10 mL) topH˜8. The mixture was stirred at 0-5° C. for 1 hour. The solid wascollected by filtration and dried under vacuum at 40° C. for 24 hours toafford the title compound 114 (0.66 g in 77% yield).

PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one(21)

To a solution of 114 (2.0 g, 5.44 mmoles) in methylene chloride (20 mL),cooled to −20° C., was added a methylene chloride solution of borontrichloride (1M, solution, 22 mL. 22 mmoles, 4.04 equivalents) over aperiod of ˜30 minutes. During addition, the temperature was maintainedat −19° to −23° C. After stirring for an additional 3 hours at −20° C.,methanol (14 mL) was added to quench the reaction. The reaction mixturewas stirred until HPLC showed no borane ester (˜4 hours). MTBE (30 mL)was added, and the reaction mixture was stirred overnight at roomtemperature. The solid obtained was filtered, washed with MTBE (˜5 mL),and dried under vacuum at room temperature to obtain 1.66 g of thehydrochloride salt of 21. The HCl salt (0.72 g, 2.29 mmoles) was takenin ˜13 mL of water and heated to ˜40° C. The pH was adjusted to ˜7 with2N NaOH. The thin slurry obtained was heated to 80-85° C. and treatedwith activated carbon (0.12 g). After 30 minutes at reflux, the hotmixture was filtered on a small Hyflo pad. The filtrate was cooled toroom temperature over 3 hours and further stirred at 0° C. for 2 hours.The crystals obtained were filtered, washed with water, and dried undervacuum to obtain the compound of formula 21 (0.32 g, 44% overall yieldfrom 114)

Isolation and Purification of Compound 21

Isolation of 21 was achieved by a resin adsorption procedure in whichthe oxidation mixture was diluted about 20 fold with water (about 1 mgof 21 per mL of diluted stream) and loaded onto SP207 resin (1 kg). Theresin bed was first washed with water to remove salt, and compound 21was eluted off the resin using 50:50 MeOH:water solution (about 20 L).The eluent, after a polish filter, was concentrated by distillationunder vacuum at a temperature less than or equal to 55° C. to a batchvolume of about 25 mL/g of 21. The resulting slurry was heated to 90° C.to form a clear solution. The clear solution was then slowly brought toambient temperature to crystallize 21. After stirring the slurry forseveral hours at ambient temperature, 21 was filtered and dried undervacuum at ambient temperature until the moisture content of the productwas between 6 and 7 wt. %. This procedure gave 21 in an average yield of75% from compound 79 and an HPLC area % of greater than 99.9.

EXAMPLE 3 PROCESS FOR THE PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one(21) PREPARATION OF[3aS-(3aα,5α,6β,6aα)]-5-(Dimethylphenylsilyl)hexahydro-6a-(hydroxymethyl)-2-oxo-2H-cyclopentoxazole-6-carboxylicacid methyl ester (67)

To a 500-mL round bottomed flask equipped with a magnetic stirrer and athermometer was charged methyl carbamate (4.5 g, 60 mmol) and MeOH (40mL) under an atmosphere of argon. The resulting solution was cooled to˜0° C. in an ice bath. Tert-butyl hypochlorite (6.52 g, 60 mmol) wasadded and the resulting mixture was stirred at 0° C. for 15 minutes. Amethanolic solution of sodium hydroxide (2.44 g of sodium hydroxide (60mmol in 40 mL MeOH) was added to this solution and the resulting mixturewas stirred at room temperature for 1 hour. The mixture was directlyconcentrated in vacuo to give a white powdery reagent. To this reagent,isopropanol (53 mL), and water (26 mL) were added. The resulting mixturewas stirred at room temperature until the mixture became a clearsolution. This mixture was cooled to ˜0° C. and then 66 (5.8 g, 20 mmol,obtained as described in Example 1) was added. The mixture was stirredfor 10 minutes and then potassium osmate hydrate (280 mg) was added. Themixture was stirred at 0° C. for 1.5 hours followed by 12 hours at roomtemperature to complete the reaction. The reaction was quenched byaddition of sodium thiosulfate (4 g) and stirred for 1 hour at roomtemperature. The mixture was filtered through a bed of diatomaceousearth (Celite®), and the filtrate diluted with water (100 mL) andextracted with ethyl acetate (3×50 mL). The organic layer was washedwith water (3×50 mL), brine (50 mL) and dried over magnesium sulfate.The organic layer was concentrated in vacuo to afford the title compound(5.9 g in 85% yield).

PREPARATION OF[3aS-(3aα,5α,6β,6aα)]-S-(Dimethylphenylsilyl)hexahydro-6a-(iodomethyl)-2-oxo-2H-cyclopentoxazole-6-carboxylicacid methyl ester (68)

To a 500-mL 3-necked round bottomed flask equipped with a magneticstirrer and a thermometer was charged 67 (33.75 g, 96.7 mmol), DCM (100mL) followed by pyridine (9.4 mL, 116 mmol) under an atmosphere ofargon. The resulting mixture was cooled to 0° C. To this stirringmixture, trifluoromethanesulfonic anhydride (19.5 mL, 116 mmol) wasslowly added over a period of 10 minutes keeping the temperature below5° C. The mixture was stirred at the same temperature for 2 hours tocomplete the reaction. The mixture was washed with HCl (1 N, 2×50 mL),water (3×50 mL), dried over magnesium sulfate, and concentrated in vacuoto afford the triflate which was used without further purification inthe next step.

The above triflate was taken in a 500-mL round bottomed flask which wascharged with acetone (100 mL) and then cooled to 0° C. To this solution,lithium iodide (25 g, 193 mmol) was added in portion-wise over a periodof 30 minutes. The mixture was stirred at room temperature for 3 hoursto complete the reaction. The mixture was directly concentrated in vacuoto remove the acetone. The resulting residue was dissolved in DCM (100mL). The solution was washed with aqueous sodium thiosulfate solution(2×100 mL), water (2×100 mL), and dried over magnesium sulfate. Theorganic layer was concentrated in vacuo to give the title compound (51.5g) as an oil.

PREPARATION OF[1R-(1α,3α,5β)]-3-Amino-3-(dimethylphenylsilyl)-2-methylene-1-cyclopentanemethanolhydrochloride (2:1) (69)

To a round bottomed flask was mixed crude 68 (10.9 g, 20.5 mmol) zincsolid (2.68 g, 2 eq, 41 mmol) in acetic acid (20 mL). The reactionmixture was heated at 100° C. for 1 h and then cooled to roomtemperature. The crude mixture was mixed with tert-butyl methyl ether(30 mL) and filtered and the cake was rinsed with tert-butyl methylether (70 mL) at room temperature. The combined filtrate was neutralizedto pH 7 with NaOH solution (1 N). The organic layer was washed withbrine (30 mL), dried (MgSO₄) and concentrated in vacuo to afford a lightyellow crude oil. This crude oil was used for the next step withoutfurther purification. The crude oil was dissolved in toluene (20 mL) andcooled to −65° C. Sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al®,65 wt. % in toluene, d=1.036, 12.3 mL) was added into the solution over˜20 min. The reaction mixture was allowed to warm up to −20° C. andstirred at −20° C. for 1 h. The reaction was quenched with NaOH (1 N, 20mL) at 0° C. and warmed to room temperature. After stirring at roomtemperature for 1.5 h, the mixture was filtered through a pad ofdiatomaceous earth (Celite®) and the cake was rinsed with tert-butylmethyl ether (100 mL). The filtrate was dried (MgSO₄) and a solution ofHCl in ether (1 N, 22 mL) was added at room temperature to precipitateout of the HCl salt. After stirring for 1 h at room temperature, the HClsalt was collected by filtration and dried under vacuum to afford 69(HCl salt, 4.4 g, 72% over 3 steps) as a beige-colored solid.

PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-6-[[4-(dimethylphenylsilyl)-3-(hydroxymethyl)-2-methylenecyclonentyl]amino]-5-nitro-4(3H)-pyrimidinone(70)

A 3-necked 500 mL round bottomed flask equipped with stirrer,temperature probe and reflux condenser was charged with the amine 69(1.49 g, 5 mmol), 2,4-diamino-5-nitropyrimidin-6-one (1.56 g, 5.35 mmol)and n-butanol (20 mL). The resultant thin slurry was subjected toheating at 40-45° C. over 15 minutes. Triethylamine (0.71 mL, 5.1 mmol)was added slowly over a period of 2 minutes. The reaction mixture wasstirred at about 70° C. for 1 h. HPLC data showed that the reaction wasalmost complete. At this point, five washes of 25 mL of water was givento the reaction mixture at 70° C. The last wash was almost colorless.The crude product, 70, in n-butanol was used without furtherpurification in the next reaction.

PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-9-[4-(dimethylphenylsilyl)-3-(hydroxymethyl)-2-methylenecyclopentyl]-1,9-dihydro-6H-purin-6-one(71)

Solid Na₂S₂O₄ (2 g, 12 mmol) was charged into the flask containing crude70 and the resulting slurry was heated to ˜60° C., over 20 minutes.Formic acid (9.5 mL, 250 mmol) was added slowly over the course of 10minutes at 65° C. The resulting mixture was stirred for 5 min and heatedto ˜70° C. for 1 hour. The mixture was cooled to 25° C. and neutralizedwith 6 N NaOH solution to effect a pH=7.04. The aqueous layer wasseparated and extracted with n-BuOH (5 mL). The combined organic layerwas filtered through a pad of diatomaceous earth and transferred into3-neck 50 mL reaction flask equipped with overhead stirrer, temperatureprobe and distillation head. The resultant solution was distilled underin vacuo to remove water and excess n-butanol to afford the pyrimidineintermediate

The resultant slurry containing the intermediate was heated to 40-50° C.and triethylorthoformate (8 mL, 48 mmol) was added over 3 minutes,followed by conc. HCl (0.2 mL) over 1 min. The reaction mixture washeated at ˜85° C. for 3 h. The reaction mixture was cooled to roomtemperature and stirred at room temperature for 12 h. The reactionmixture was neutralized to a pH of ˜7.2 with aqueous NaOH solution. Theresulting crude product over an ion exchange column to give the product71 (1.25 g) in ˜65% yield.

The compound of formula 70 could then be converted to the compound offormula 21 as described in the Example 1.

EXAMPLE 4 PROCESS FOR THE PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one(21) PREPARATION OF(4S,5R)-4-(Phenylmethoxy)-5-[(phenylmethoxy)methyl]-1-cyclopentene-1-methanol(16)

To a round bottomed flask equipped with an argon inlet, magnetic stirrerand cooling bath was dissolved(4S,5R)-4-(Phenylmethoxy)-5-[(phenylmethoxy)methyl]-1-cyclopentene-1-carboxylicacid methyl ester 7 (3.62 g, 10.2 mmol) in DCM (40 mL). The solution wascooled to −78° C. and diisobutylaluminum hydride (1 M in toluene, 22.4mL, 22.4 mmol) was added into the solution over the course of 10minutes. After stirring at −78° C. for 1 hour the reaction mixture wasquenched with a saturated solution of potassium sodium tartrate(Rochelle salt, 50 mL) and stirred at room temperature overnight. Theorganic layer was diluted with ethyl acetate, separated, dried (sodiumsulfate) and concentrated in vacuo to afford the crude allylic alcoholas colorless oil (3.06 g, 90%). After standing at room temperature thetitle compound crystallized out as a white solid.

PREPARATION OF[1R-(1α,2α,3β,5α)]-3-(Phenylmethoxy)-2-[(phenylmethoxy)methyl]-6-oxabicyclo[3.1.0]hexane-1-methanol(17)

To a flame dried round bottomed flask equipped with an argon inlet,magnetic stirrer and cooling bath was added (−)-(D)-diethyltartrate (188mg, 0.91 mmol) and 4A molecular sieves (flame dried, 1.45 g) in DCM (10mL). The reaction suspension was cooled to −25° C. and titanium (IV)isopropoxide (0.20 mL, 0.69 mmol) was added into the suspension. Thereaction mixture was stirred at −25° C. for 1 hour and then tert-butylhydroperoxide (3 M in octane, 1.52 mL, 4.5 mmol) was added. Afterstirring the mixture for about 1.5 hours at −25° C., 16 (0.73 g, 2.28mmol in 4 mL DCM) was added into the solution over the course of 10minutes. The reaction mixture was stirred at −25° C. for 3-4 hours andquenched with sodium hydroxide (5 N, 2 mL). The mixture was stirred for1 hour at room temperature and filtered through a bed of diatomaceousearth (Celite®). The bed was rinsed with DCM (2×10 mL). The combinedorganic layer was washed with brine (20 mL), dried (sodium sulfate) andconcentrated in vacuo to afford (0.76 g, ˜100%) a colorless oil. Flashcolumn chromatography (2:1 to 1:1 hexane/ethyl acetate) gave 0.55 g ofthe title compound (73%) as a light yellow solid (mp 60-62° C.).

PREPARATION OF[1S-(1α,2β,3α,5β)]-5-[2-Amino-6-(phenylmethoxy)-9H-purin-9-yl]-1-hydroxy-3-(phenylmethoxy)-2-(phenylmethoxy)methyl]cyclopentanemethanol(18, X=BnO)

To a round bottomed flask equipped with an argon inlet, a magneticstirrer and a reflux condensor were charged 2-amino-6-O-benzyloxypurine(1.66 g, 6.87 mmol) with dimethylformamide (20 mL). Lithium hydride(32.7 mg, 4.13 mmol)) was added into the suspension, and the resultingmixture was stirred for 1 hour. A solution of 17 (2.13 g in 2 mLdimethylformamide, 6.25 mmol) was added into the solution. The solutionwas heated to 120-130° C. for 1 hour. The resulting solution was workedup by quenching with sodium hydroxide (1 N, 20 mL), and extracting withethyl acetate (2×150 mL). The combined organic layer was washed withsaturated ammonium chloride solution (200 mL) and brine (100 mL), dried(sodium sulfate), and concentrated in vacuo to afford a light brownsolid. This solid was dissolved in ethyl acetate/DCM and passed througha pad of flash silica gel (eluted with ethyl acetate) to afford 3.1 g ofthe title compound (85%) as light yellow solid. Recrystallization (ethylacetate/hexanes) gave 2.81 g of the title compound in ˜78% yield as anoff white solid.

PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[2-methylene-4-(phenylmethoxy)-3-[(phenylmethoxy)methyl]cyclopentyl]-6H-purin-6-one(20)

A 1-L round bottomed flask equipped with an argon inlet, and a magneticstirrer was charged with 18 (2.6 g, 4.4 mmol), trimethyl orthoformate(2.38 mL, 21.8 mmol), pyridinium p-toluenesulfonate (0.56 g, 2.22 mmol),and DCM (20 mL). The reaction mixture was stirred for about 16 hours atroom temperature. After the completion of the reaction, the reactionmixture was quenched with sodium bicarbonate solution (50 mL). Theresulting mixture was extracted with ethyl acetate (2×50 mL) and thecombined organic layer was washed with brine (50 mL), dried (sodiumsulfate), and concentrated in vacuo to afford the orthoformateintermediate. The crude product was dissolved with acetic acid/aceticanhydride (1.5 mL/30 mL) in a round bottomed flask. The solution washeated to reflux for about 5 hours and then cooled to room temperature.The acetic acid/acetic anhydride was removed by vacuum distillation toafford an intermediate mixture (2.34 g). The above intermediate mixture(2.2 g, 3.7 mmol) was dissolved in acetonitrile (60 mL) and 2 N HCl (30mL), and then heated to reflux to complete the reaction. The mixture wascooled to room temperature and neutralized by addition of triethylamine.The mixture was directly concentrated in vacuo to remove most ofacetonitrile. Ethanol was added to the resulting solid residue and thesuspension was stirred for 1 hour. The solid was collected byfiltration, rinsed with ethanol, and dried under high vacuum to afford1.57 g of the title compound in 93% yield.

PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one(21)

To a round bottomed flask equipped with magnetic stirrer and nitrogeninlet-outlet were mixed 20 (2.7 g, 5.9 mmol) with CH₂Cl₂ (10 mL). Themixture was cooled to −78° C. and BCl₃ (1 M, 35.4 mL, 35.4 mmol) wasadded into the reaction suspension at a rate so that the reactiontemperature did not exceed −65° C. The reaction mixture was stirred at−78° C. for 0.5 h and then it was warmed up to −20° C. After stirring at−20° C. for 1 h, the reaction mixture was re-cooled to −78° C. and MeOH(30 mL) was added into the reaction mixture and warmed to roomtemperature. The reaction mixture was concentrated in vacuo to removeMeOH to afford a light yellow oil. This oil was re dissolved in MeOH (30mL); Decolorizing carbon (2.7 g) was added into the solution and stirredat room temperature for 0.5 h. The suspension was filtered throughdiatomaceous earth and the cake was rinsed with MeOH (10 mL). Thecombined filtrate was concentrated in vacuo to afford a clear oil. Thisoil was dissolved in water (20 mL) and extracted with ethyl acetate(2×30 mL). The aqueous layer was neutralized by addition of NaOH toeffect a pH ˜7.2. The solid from the suspension was collected byfiltration and recrystallized with water (30 mL) to afford 1.36 g of 21.

EXAMPLE 5 PROCESS FOR THE PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one(21) PREPARATION OF COMPOUND(1α,2β,3α)-2-[(Phenylmethoxy)methyl]-4-cyclopentene-1,3-diol diacetateester (2)

To a round bottomed flask equipped with magnetic stirrer was dissolved 1(2.2 g, 10 mmol) in acetic anhydride (4 mL) and pyridine (2.5 mL). Afterstirring at room temperature overnight, the excess acetic anhydride andpyridine was removed by vacuum distillation, the crude oil waschromatographed (silica, 2:1 Hexane/EtOAc) to afford 2.8 g (92%) of 2 aslight yellow oil.

PREPARATION OF(+)-(1α,2β,3α)-2-[(Phenylmethoxy)methyl]-4-cyclopentene-1,3-diolmonoacetate ester (3) (without immobilization of the enzyme)

Enantioselctive asymmetric hydrolysis of the diacetate 2 was carried outusing the enzyme Pancreatin or Lipase PS-30 from Pseudomonas cepacia.The reaction mixture contained 25 mM potassium phosphate buffer (36 mL,pH 7.0), toluene (4 mL) and the diacetate 2 (2 mg/mL) and Lipase PS-30or Pancreatin (50 mg/mL). The reaction was carried out at 25° C.,maintaining the pH at 7.0 by addition of 1 N NaOH as required. Theprogress of the reaction was monitored by high pressure liquidchromatography. The reaction was terminated when the concentration ofthe remaining substrate 2 dropped below 0.05 mg/mL. The reaction mixturewas concentrated under reduced pressure to obtain (+)-monoacetate 3.After 16 h of reaction time, a reaction yield of 80 M % and an ee of 98%was obtained using Lipase PS-30. A reaction yield of 75% and an ee of98.5% was obtained using Pancreatin.

PREPARATION OF(+)-(1α,2β,3α)-2-[(Phenylmethoxy)methyl]-4-cyclopentene-1,3-diolmonoacetate ester (3) (using immobilized Lipase PS-30)

Enantioselective asymmetric hydrolysis of diacetate 2 was carried outusing immobilized Lipase PS-30. Crude Lipase PS-30 from Pseudomonascepacia was immobilized on polypropylene (Accurel Systems InternationalCorp.) and immobilized enzyme was used. The reaction contained 25 mMpotassium phosphate buffer (1.8 L, pH 7.0), toluene (200 mL), diacetate2 (52 g), and immobilized Lipase PS-30 (180 g). After 18 h reactiontime, a reaction of 80 M % (32.5 g) and ee of 98% were obtained for the(+)-monoacetate 3. At the end of the reaction, the immobilized enzymewas filtered and the clear supernatant obtained was extracted with twovolumes of ethyl acetate. The separated organic phase was concentratedunder reduced pressure to obtain the desired product 3.

PREPARATION OF[1S-(1α,4α,5β)]-4-[Nitro(phenylsulfonyl)methyl]-5-[(phenylmethoxy)methyl]-2-cyclopenten-1-ol(4)

To a round bottomed flask equipped with an argon inlet, magneticstirrer, addition funnel and reflux condensor was added compound 3 (0.98g, 3.74 mmol), phenylsulfonylnitromethane (0.91 g, 4.5 mmol) andtetrakis[triphenylphosphine]-palladium (43 mg, 0.037 mmol) in THF (7 mL)at 0° C. The reaction mixture was degassed using argon for a fewminutes. Triethylamine (1.1 g, 1.6 mL, 11.4 mmol) was added into thereaction mixture over the course of 2 minutes at 0° C. The reactionmixture was stirred at 0° C. for 1 hour and allowed to warm up to roomtemperature. The reaction mixture was then stirred at room temperaturefor 3 hours. The reaction mixture was quenched with 1 N HCl at 0° C. (15mL) and extracted with hexane/ethyl acetate (1:1; 2×20 mL). The combinedorganic layer was washed with brine (30 mL), dried (sodium sulfate) andconcentrated in vacuo to afford a red-colored oily residue (2.2 g).Silica pad filtration was performed to remove the baseline materials togive the title compound (1.36 g).

PREPARATION OF[1R-(1α,4α,5β)]-[[Nitro[4-(phenylmethoxy)-5-[(phenylmethoxy)methyl-2-cyclopenten-1-yl]methyl]sulfonyl]benzene(5)

To a round bottomed flask with an argon inlet, a magnetic stirrer and acooling bath was charged 4 (3.0 g, 7.43 mmol) in THF at 0° C. Sodiumhydride (60% suspension in mineral oil, 0.68 g, 17 mmol) was added intothe reaction mixture portion-wise over the course of 10 minutes withstirring. The resulting suspension was stirred at 0° for 30 minutes,warmed to room temperature, and stirred for 1 hour at room temperature.Benzyl bromide (1.52 g, 1.06 mL, 8.91 mmol) was added and the reactionmixture was heated at 45° C. for 3 hours to complete the reaction. Thereaction was quenched with cold HCl (1 N, 30 mL) and extracted withethyl acetate (2×30 mL). The combined organic layer was washed withbrine (30 mL), dried (sodium sulfate), and concentrated in vacuo toafford the title compound as a light brown oil (3.98 g). The crudeproduct was used without further purification in the next step.

PREPARATION OF(4S,5R)-4-(Phenylmethoxy)-5-[(phenylmethoxy)methyl]-1-cyclopentene-1-carboxylicacid methyl ester (7)

To a round bottomed flask equipped with an argon inlet, a magneticstirrer, an addition funnel and a reflux condensor was added 5 (2.7 g,5.47 mmol) and sodium carbonate (2.58 g, 46 mmol) in a mixture ofDCM/MeOH (3:1, 10 mL) at room temperature. The reaction mixture washeated to reflux and a solution of potassiumperoxymonosulfate:tetrabutyl ammonium salt (2.3% active oxygen, 11 g in15 mL of DCM, 7.9 mmol) in DCM was added into the reaction suspensiondropwise over a period of 10 hours. After refluxing for about 14 hours,the reaction mixture was cooled to room temperature and diluted withMeOH (50 mL). The resulting mixture was cooled to −40° C. Concentratedsulfuric acid was added to neutralize the reaction medium to acidic pH(1.2 mL was used). The reaction mixture was warmed up to roomtemperature and stirred at room temperature for 3 hours. The reactionmixture was quenched with water/brine (1:1; 40 mL) and extracted withhexane/ethyl acetate (2:1, 2×200 mL). The combined organic layer waswashed with saturated sodium bicarbonate solution (100 mL) and brine(100 mL), dried (sodium sulfate) and concentrated in vacuo to affordcrude intermediate (1.88 g, >100% material balance) which was used inthe next step without any further purification.

To a round bottomed flask equipped with an argon inlet and a magneticstirrer was dissolved the above obtained intermediate (2.95 g, 8.1 mmol)in dry MeOH (10 mL). A sodium methoxide solution in MeOH solution (25wt. %, 0.34 g, 1.6 mmol) was added at room temperature. The reactionmixture was stirred at room temperature for 2 hours. After completion,the reaction mixture was neutralized with HCl (10 mL) at 0° C., andextracted with ethyl acetate/hexane (1:1; 2×100 mL). The combinedorganic layer was washed with brine, dried (sodium sulfate), andconcentrated in vacuo to afford a solid. Recrystallization withhexane/tert-butyl methyl ether (10:1) at −20 to −30° C. gave 1.83 g ofthe title compound in 64% yield as a light yellow solid.

EXAMPLE 6 PROCESS FOR THE PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one(21) PREPARATION OF(−)-(1α,2β,3α)-2-[(Phenylmethoxy)methyl]-4-cyclopentene-1,3-diolmonoacetate ester (13) (without immobilization of the enzyme)

Enantioselective acetylation of the diol 1 was carried out usingimmobilized Lipase PS-30 from Pseudomonas cepacia. The reaction mixturecontained heptane/t-butyl methyl ether (10/1 v/v, 1 L), diol 1 (5 g),immobilized Lipase PS-30 (25 g), and isopropenyl acetate (2 eq) as theacylating agent. The reaction was carried out at 33° C. The progress ofthe reaction was monitored by high pressure liquid chromatography. Thereaction was terminated when the concentration of the remainingsubstrate 1 dropped below 0.1 mg/mL. After 4 h, a reaction yield of 80%and an ee of 98% was obtained for the (−)-monoacetate 13.

PREPARATION OF [1R-(1α,4α,5β)]-Carbonic acid, methyl4-(acetoxy)-5-[(phenylmethoxy)methyl]-2-cyclopenten-1-yl ester (10)

To a round bottomed flask equipped with magnetic stirrer and N₂inlet-outlet were mixed 13 (2.62 g, 10 mmol), pyridine (1.18 g, 12 mmol)with CH₂Cl₂ (5 mL). The mixture was cooled to −5° C. and methylchloroformate (1.134 g, 12 mmol) was added into the reaction suspensionat a rate so that the reaction temperature did not exceed 0° C. Thereaction mixture was stirred at 0° C. for 1 h and warmed up to roomtemperature for 1 h. The resulting mixture was quenched with saturatedammonium chloride solution at 0° C. The quenched solution was extractedwith 1:2 EtOAc/hexane (30 mL×2). The combined organic layer was washedwith brine (30 mL); dried (Na₂SO₄); concentrated in vacuo, and driedunder high vacuum to afford crude 14 (3.32 g, 100%) as light brown oil.It was used in the next reaction without further purification.

PREPARATION OF[1R-(1α,4α,5β)]-[[Nitro[4-(acetoxy)-5-[(phenylmethoxy)methyl]-2-cyclopenten-1-yl]methyl]sulfonyl]benzene(15)

To a round-bottomed flask equipped with magnetic stirrer was dissolvedphenylsufonylnitromethane (2.41 g, 12 mmol) in dry THF (25 mL). At 0°C., sodium hydride (0.46 g, 60% mineral oil dispersion, 12 mmol) wasadded over 5 min. After warming up to room temperature and stirred atroom temperature for 1 h, crude 14 (3.3 g, 10 mmol in 5 mL of THF) wasadded over 10 min. The reaction was stirred at room temperature for 30min and at 50° C. for 1 h. The reaction mixture was worked up by theaddition of saturated ammonium chloride solution (30 mL) followed byextraction with ethyl acetate (2×40 mL). The combined organic phase waswashed with brine (30 mL); dried (Na₂SO₄) and concentrated in vacuo toafford 15 as a crude brown oil (5.12 g, >100%) which was used in thenext step without purification.

PREPARATION OF[1R-(1α,4α,5β)]-[[Nitro[4-(hydroxy)-5-[(phenylmethoxy)methyl]-2-cyclopenten-1-yl]methyl]sulfonyl]benzene(4)

To a round bottomed flask equipped with magnetic stirrer was dissolvedcrude 15 (5.12 g, 10 mmol) in 25 mL MeOH. Potassium carbonate (140 mg, 1mmol) was added into the flask at room temperature and the resultingmixture was stirred overnight. The reaction mixture was concentrated invacuo to remove MeOH. The concentrate was extracted with ethyl acetate(2×30 mL) and saturated ammonium chloride solution (30 mL). The combinedorganic layer was washed with brine (20 mL); dried (Na₂SO₄) andconcentrated in vacuo to afford a light brown oil. Flash columnchromatography (1:2 to 1:1 EtOAc/hexane) afford 2.92 g of 4 (73%) as acolorless oil.

EXAMPLE 7 PROCESS FOR THE PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one(21) PREPARATION OF[1R-(1α,4α,5β)]-4-(Phenylmethoxy)-5-[(phenylmethoxy)methyl]-2-cyclopenten-1-ol(9) (R′=Bn)

To a round bottomed flask equipped with an argon inlet, a magneticstirrer, a cooling condensor, and an oil bath was charged[1S-(1α,2α,3β,5α)]1-3-(Phenylmethoxy)-2-[(phenylmethoxy)methyl]-6-oxabicyclo[3.1.0]hexane8 (20.19 g, 65 mmol, as prepared in U.S. Pat. No. 5,206,244, hereinincorporated by reference) in THF (150 mL). Lithium hexamethyldisilazide(1 M in hexane, 190 mL, 190 mmol) was added into the solution at roomtemperature. The reaction mixture was heated at 60° C. for 1.5 hours.The resulting solution was cooled to room temperature and diluted withMeOH (200 mL). After stirring for 20 minutes at room temperature, thereaction mixture was quenched with HCl (1 N, 300 mL), and extracted withethyl acetate (3×300 mL). The combined organic layer was washed withbrine (2×200 mL), dried (sodium sulfate), and concentrated in vacuo toafford 22.7 g of the title compound (>100% material balance) which wasused in the next step without any further purification.

PREPARATION OF [1R-(1α,4α,5β)]-Carbonic acid, methyl4-(phenylmethoxy)-5-[(phenylmethoxy)methyl]-2-cyclopenten-1-yl ester(10)

To a round bottomed flask equipped with an argon inlet, a magneticstirrer and a cooling bath was charged crude 9 (12.3 g, 39.6 mmol) andpyridine (9.7 mL, 120 mmol) in DCM (100 mL). The solution was cooled to−20 to −15° C. and methyl chloroformate (4.2 g, 3.41 mL, 44 mmol) wasadded into the solution over the course of 20 minutes. The reactionmixture was stirred at −15° C. for 0.5 hour and then slowly warmed toroom temperature to complete the reaction. The resulting mixture wasquenched with HCl (2 N, 120 mL) at 0° C. and extracted with ethylacetate (2×300 mL). The combined organic layer was washed with brine(200 mL), dried (sodium sulfate), concentrated in vacuo, and dried underhigh vacuum to afford the crude title compound as a brown oil which wasused in the next step without any further purification.

PREPARATION OF[1R-(1α,4α,5β)]-[[Nitro[4-(phenylmethoxy)-5-[(phenylmethoxy)methyl]-2-cyclopenten-1-yl]methyl]sulfonyl]benzene(5)

To a round bottomed flask equipped with an argon inlet, a magneticstirrer and a cooling bath was dissolved crude 10 (9.8 g, 26.5 mmol),phenylsulfonylnitromethane (5.4 g, 26.8 mmol) andtetrakis(triphenylphosphine)palladium (0.6 g, 0.52 mmol) in THF (80 mL)at 0° C. The reaction mixture was degassed using argon for a fewminutes. Triethylamine (8.4 g, 11.1 mL, 79.5 mmol) was added to thereaction mixture over the course of 10 minutes at 0° C. The reactionmixture was stirred at 0° C. for 1 hour and allowed to warm to roomtemperature. The reaction mixture was stirred at room temperature for 3hours. The reaction mixture was then quenched with 2 N HCl at 0° C. (100mL) and extracted with hexane/ethyl acetate (1:1; 2×30 mL). The combinedorganic layer was washed with brine (100 mL), dried (sodium sulfate),and concentrated in vacuo to afford a red-colored oily residue. Silicapad filtration was conducted using ethyl acetate to remove the baselinematerials and give the title compound (14.2 g crude, >100%) as a lightbrown oil which was used in the next step without any furtherpurification.

The conversion of compound of formula 5 to the ester of formula 7 isdescribed in Example 5.

EXAMPLE 8 PROCESS FOR THE PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one(21) PREPARATION OF(4S,5R)-4-(Phenylmethoxy)-5-[(phenylmethoxy)methyl]-2-cyclopenten-1-one(80)

To a round bottomed flask equipped with an argon inlet, magnetic stirrerwere mixed with molecular sieves (4 g); pyridinium dichromate (4.16 g,20 mmol) and HOAc (0.60 g, 10 mmol) with CH₂Cl₂ (25 mL) at 0° C. andstirred for 1 h. Allylic alcohol 9 (3.11 g, 10 mmol, prepared accordingto Example 7) in CH₂Cl₂ (5 mL) was added into the flask over ˜5 min.After stirring for 2.5 h at 0° C., the reaction mixture was filteredthrough a pad of silica gel and the cake was rinsed with 1:3CH₂Cl₂/EtOAc. The resulting filtrate was extracted with HCl (1 N, 40mL)/EtOAc (50 mL). The organic layer was dried (Na₂SO₄) and concentratedin vacuo to afford a brown oil. This brown oil was chromatographed with1:2 EtOAc/Hexane to afford 80 (2.85 g, 92%) of light yellow oil

PREPARATION OF (4S,5R)-Trifluoromethanesulfonic acid4-(phenylmethoxy)-5-[(phenylmethoxy)methyl]-1-cyclopenten-1-yl ester(81)

To a round bottomed flask equipped with an argon inlet, magnetic stirrerwere mixed with 80 (1.7 g, 5.5 mmol) with THF (15 mL) and cooled to −78°C. Lithium tri-sec-butylborohydride (L-Selectride®) (1 M in THF, 5.5 mL,5.5 mmol) was added over ˜20 min. at −78° C. The reaction mixture wasstirred at −78° C. for 1.5 h and N-phenyltrifluoromethanesulfonimide(1.98 g, 5.5 mmol) was added at −78° C. After stirring at −78° C. for 1h, the reaction mixture was allowed to slowly warm up to roomtemperature and stirred at room temperature overnight. The resultingmixture was worked up with saturated NH₄Cl solution (30 mL) andextracted with EtOAc (52 mL). The emulsion was filtered through a pad ofdiatomaceous earth and washed with EtOAc (20 mL) the combined organiclayer was dried (Na₂SO₄) and concentrated in vacuo to afford a brown oil(3.2 g, 100%). This brown oil was used in the next reaction withoutfurther purification.

PREPARATION OF(4S,5R)-4-(Phenylmethoxy)-5-[(phenylmethoxy)methyl]-1-cyclopentene-1-carboxylicacid methyl ester (7)

To a round bottomed flask equipped with an argon inlet, magnetic stirrerwere mixed crude 81 (3.2 g, 5.5 mmol) DMF (25 mL); MeOH (10 mL) andtriethylamine (1.54 mL, 11 mmol). Pd(Ph₃)₄ (635 mg, 0.55 mmol) was addedinto the solution and the resulting mixture degassed 3 times with COgas. The reaction was stirred at 1 atmosphere of CO gas at roomtemperature for 2 h. TLC showed no the absence of starting material. Thereaction was worked up with NaOH (0.5 N, 100 mL) at room temperature andextracted with EtOAc (2×50 mL). The combined EtOAc layer was washed withbrine (50 mL); dried (Na₂SO₄) and concentrated in vacuo to afford alight yellow oil. Flash column chromatography (1:2 hexane/EtOAc) gave 7(1.36 g, 70% over 4 steps).

EXAMPLE 9 PROCESS FOR THE PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one(21) PREPARATION OF[1R-(1α,4α,5β)]-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-[(phenylmethoxy)methyl]-2-cyclopenten-1-olacetate ester (22)

To a round bottomed flask equipped with a nitrogen inlet was dissolvedcompound 3 (1.85 g, 7.05 mmol) in CH₂Cl₂ (10 mL), and the resultingsolution was cooled to 0° C. To the reaction mixture was addedtriethylamine (1.43 g, 2 mL, 14.1 mmol), 4-N,N-dimethylaminopyridine(DMAP, ˜100 mg) and tert-butyldimethyl chlorosilane (1.17 g, 7.75 mmol)at 0° C. The resulting mixture was warmed to room temperature andstirred overnight. The resulting mixture was worked up by addition ofNaOH solution (0.5 N, 20 mL) at 10° C. and extracted with a solution ofethyl acetate/hexanes (1:2 v/v, 2×30 mL). The combined organic layer waswashed with brine (30 mL), dried (Na₂SO₄), and concentrated in vacuo tocompound 22 as a crude light oil.

PREPARATION OF[1R-(1α,4α,5β)]-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-[(phenylmethoxy)methyl]-2-cyclopenten-1-ol(9)

The above obtained compound 22 was dissolved in MeOH (30 mL), andpotassium carbonate (150 mg) was added at room temperature. Afterstirring at room temperature for 5 h, the MeOH was removed byconcentrating the reaction mixture in vacuo. The resulting mixture wasextracted with ethyl acetate/hexanes (1:2 v/v, 2×30 mL) and saturatedNH₄Cl solution (20 mL). The combined organic layer was washed with brine(30 mL), dried (Na₂SO₄), and concentrated in vacuo to afford a lightyellow oil. The oil was further purified by flash column chromatography(hexanes/ethyl acetate 8:1 to 3:1) to afford compound 9 (2.28 g, 97%overall from compound 3).

PREPARATION OF(4S,5R)-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-[(phenylmethoxy)methyl]-2-cyclopenten-1-one(80)

To a 250-mL 3-necked flask, oven dried and equipped with a mechanicalstirrer was charged with pyridinium dichromate (20.24 g, 53.80 mmol),molecular sieves (oven dried) and DCM (40 mL). The resulting slurry wascooled to 0° C. and to this slurry, acetic acid (which had been driedover molecular sieves, 1.61 g, 26.90 mmol) was charged. The resultingmixture was stirred for 30 minutes at 0° C. 9 (10 g, 29.89 mmol) in DCM(10 mL) was added to the reaction mixture over a period of 10 minutes.The resulting reddish colored reaction mixture was stirred for 2 hoursat 0° C. After the reaction was completed, ethyl acetate (100 mL),acetonitrile (5 mL), and diatomaceous earth (Celite®, 5 g) were addedsequentially, and the resulting mixture was stirred for 10 minutes. Theslurry was filtered on a bed of diatomaceous earth (Celite®) to give adark colored filtrate. The filtrate was washed with 5% aqueous NaHSO₃(2×250 mL) followed by water (100 mL). The organic layer was dried overmagnesium sulfate and the solvent was concentrated in vacuo to give 9.5g of the title compound as a dark transparent, brown oil.

PREPARATION OF (4S,5R)-Trifluoromethanesulfonic acid4-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5-[(phenylmethoxy)methyl]-1-cyclopenten-1-ylester (81)

An oven dried 250-mL 3-necked round bottomed flask, equipped with amechanical stirrer and an argon inlet, was charged with 80 (9.5 g, 29.89mmol) and THF (10 mL). The resulting mixture was cooled to −78° C.Lithium tri-sec-butylborohydride (L-Selectride®) (1 M, 6.25 g, 32.88mmol) in THF (20 mL) was added over a 20 minute period. To this reactionmixture, N-phenyltriflimide (10.46 g, 29.29 mmol) in THF (20 mL) wasadded over a period of 5 minutes, keeping the reaction temperature below−78° C. The reaction mixture was stirred overnight while allowing it towarm to room temperature. Tert-butyl methyl ether (100 mL) was added tothe reaction mixture and the resulting organic layer was washed withsaturated aqueous sodium bicarbonate solution (2×75 mL) followed bybrine (5 mL). The organic layer was dried over magnesium sulfate andconcentrated in vacuo to give the title compound (27 g) as yellow oil.

PREPARATION OF(4S,5R)-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-[(phenylmethoxy)methyl]-1-cyclopentene-1-carboxylicacid methyl ester (7)

A 250-mL 3-necked round bottomed flask equipped with a mechanicalstirrer was charged with 81 (27.0 g, 29.89 mmol), dimethylformamide (20mL), MeOH (20 mL) and triethylamine (20.74 mL, 149.45 mmol). Thereaction mixture was flushed three times with argon. To this mixture wasadded tetrakis(triphenylphosphine) (1.762 g, 1.49 mmol). The reactionmixture was flushed three times with carbon monoxide. The reactionmixture was stirred at room temperature for 18 hours under an atmosphereof carbon monoxide. The reaction mixture was extracted with tert-butylmethyl ether (200 mL) and the reddish mixture was filtered on a bed ofdiatomaceous earth (Celite®). The filtrate was concentrated in vacuo togive 30 g of a blackish colored oil which upon column chromatographypurification gave the title compound as an oil (4.5 g, 40% yield overallyield from 23).

EXAMPLE 10 PROCESS FOR THE PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one(21) PREPARATION OF COMPOUND(4S,5R)-4-[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-[(phenylmethoxy)methyl]-1-cyclopentene-1-methanol(16)

A 500-mL 3-necked round bottomed flask, equipped with an argon inlet, atemperature probe, and a mechanical stirrer, was charged with(4S,R)-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-[(phenylmethoxy)methyl]-1-cyclopentene-1-carboxylicacid methyl ester (7) (10 g, 26.55 mmol, as prepared in Example 9) inDCM (200 mL). The solution was cooled to −78° C. and to this solutiondiisobutylaluminum hydride (1 M, 66.39 mL, 66.375 mmol in toluene) wasadded slowly. The reaction mixture was stirred at −78° C. for 2 hours tocomplete the reaction. The reaction mixture was poured into saturatedsolution of potassium sodium tartrate (400 mL). The mixture was stirredfor 2 hours. The organic layer was separated and the aqueous layer wasextracted with n-hexane (200 mL). The combined organic layer was washedwith water (50 mL), dried over magnesium sulfate, and concentrated invacuo to give the title compound (9.3 g) as a yellowish oil.

PREPARATION OF[1R-(1α,2α,3β,5α)]-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-2-[(phenylmethoxy)methyl]-6-oxabicyclo[3.1.0]hexane-1-methanol(17)

A 250-mL oven dried three necked round bottomed flask was equipped witha magnetic stir bar, argon inlet, and temperature probe charged withoven dried powdered molecular sieves 4A° (9.0 g). DCM (30 mL) was addedto the flask and the resulting suspension was stirred room temperaturefor 5 minutes. Diethyl D-tartrate (2.13 g, 10.32 mmol) in DCM (18 mL)was added at room temperature and the mixture was cooled to −30° C.Keeping the temperature at −30° C., titanium (IV) isopropoxide (2.665mL, 9.03 mmol) was added. The reaction mixture was stirred at −30° C.for 30 minutes followed by 15 minutes at −15° C. The mixture was cooledto −30° C. To this mixture, a solution of compound 16 (4.5 g, 12.9 mmol)in DCM (18 mL) was added. The mixture was stirred for 30 minutes at −30°C. followed by addition of a solution of tert-butyl hydroperoxide(5.0-6.0 M; 9.40 mL, 5.176 mmol). The reaction mixture was stirredbetween −30° C. to −20° C. for 3 hours to complete the reaction. Thereaction was quenched by addition of water (45 mL). The reaction mixturewas stirred with vigorous mixing and allowed to warm up to roomtemperature (15 to 20° C.). When the temperature reached ˜15° C., 30%sodium hydroxide solution (10 mL) was added slowly to give a milky whiteslurry. This slurry was added into a 3.0-L Erlenmeyer flask containingtert-butyl methyl ether (1100 mL). The mixture was stirred for 30minutes and then filtered on a bed of diatomaceous earth (Celite®). Theaqueous layer was separated from the filtrate and discarded. The organiclayer was washed with 10% aqueous sodium thiosulfate (100 mL) and water(2×160 mL). The combined organic layer was washed with water (100 mL),brine (50 mL), and dried over magnesium sulfate. The organic layer wasconcentrated in vacuo to give the title compound in quantitative yield(5.47 g) as an oil.

PREPARATION OF COMPOUND[1S-(1α,2α,4β,5α)]-5-[2-Amino-6-(phenylmethoxy)-9H-purin-9-yl]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-hydroxy-2-[(phenylmethoxy)methyl]cyclopentanemethanol(18)

To a round bottomed flask equipped with an argon inlet, magnetic stirrerand refluxing condenser were charged O-benzyloxy guanine (1.66 g, 6.87mmol) with DMF (20 mL). LiH (32.7 mg, 4.13 mmol)) was added into thesuspension and stirred for 1 h. A solution of 17 (2.13 g in 2 mL DMF,6.25 mmol) was added into the solution and heated to 120-130° C. for 1h. The resulting solution was worked up by quenching with NaOH (1 N, 20mL) and extracted with EtOAc (2×150 mL). The combined organic layer waswashed with saturated NH₄Cl (200 mL), brine (100 mL), dried (Na₂SO₄) andconcentrated in vacuum to afford a light brown solid. This solid wasdissolved in EtOAc/CH₂Cl₂ and passed through a pad of flash silica gel(eluted with EtOAc) to afford 3.102 g of 18 (85%) as light yellow solid.Recrystallization (EtOAc/Hex.) gave 2.6 g (1st crop, 72%) and 0.21 g(2nd crop, 5.8%) of 18 as an off white solid.

PREPARATION OF[1S-(1α,2β,4β)]-4-[2-Amino-6-(phenylmethoxy)-9H-purin-9-yl]-3-methylene-2-[(phenylmethoxy)methyl]cyclopentanol(19)

A round bottomed flask equipped with an argon inlet, magnetic stirrerwas charged 18 (2.6 g, 4.4 mmol), trimethylorthoformate (2.38 mL, 21.8mmol), pyridinium p-toluenesulfonate (0.56 g, 2.22 mmol) and CH₂Cl₂ (20mL). The reaction mixture was stirred for about 16 h at roomtemperature. After the completion of the reaction, the reaction mixturewas quenched with NaHCO₃ (50 mL). The resulting mixture was extractedwith EtOAc (2×50 mL) and the combined organic layer was washed withbrine (50 mL), dried (Na₂SO₄) and concentrated in vacuo to afford theorthoformate. The crude product was dissolved with HOAc/Ac₂O (1.5 mL/30mL) in a round bottomed flask and heated to reflux for about 5 h. Themixture was then cooled to room temperature. The HOAc/Ac₂O was removedby vacuum distillation to afford a light brown oil. The crude productwas purified by a silica pad filtration to afford 2.34 g of a mixture.

PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-2-methylene-3-[(phenylmethoxy)methyl]cyclopentyl]-6H-purin-6-one(20)

The above mixture (2.2 g, 3.7 mmol) was dissolved in CH₃CN (60 mL) and 2N HCl (30 mL) and the resulting solution was heated to reflux. Thereaction mixture was monitored by HPLC. After the completion of thereaction, the mixture was cooled to room temperature and neutralized byaddition of triethylamine. The mixture was directly concentrated invacuo to remove most of CH₃CN. Ethanol was added to the resulting solidresidue, and the suspension was stirred for 1 h. The resulting solid wascollected by filtration. The solid was rinsed with EtOH and dried underhigh vacuum to afford 1.57 g of 20.

The compound of formula 20 was then converted to the compound of formula21 according to the procedure described in Example 4.

EXAMPLE 11 PROCESS FOR THE PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one(21) PREPARATION OF(4S)-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-2-cyclopenten-1-one (33)

To a 1-L round bottomed flask was charged(4S)-4-Hydroxy-2-cyclopenten-1-one (32) (20 g, 204 mmol, prepareddescribed in Khanapure, S.; Najafi, N.; Manna, S.; Yang, J.; Rokash. J.J. Org. Chem., 1995, 60, 7448) in DCM (200 mL) followed byN,N-dimethylethylamine (47.7 g, 653 mmol), tert-butyldimethylsilylchloride (46.1 g, 306 mmol) and a catalytic amount of4-N,N-dimethylaminopyridine (1 g). The mixture was stirred at roomtemperature for 24 hours. The reaction mixture was poured into ethylacetate (200 mL) and the organic layer washed with water (200 mL),aqueous HCl (1 N, 2×100 mL), brine (100 mL) and saturated sodiumbicarbonate solution (100 mL). The organic layer was dried overmagnesium sulfate and concentrated in vacuo to afford the title compoundas a crude product (42 g, ˜98% yield).

PREPARATION OF(3S,4S)-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-3-[(dimethylphenylsilyl)methyl]-1-[(trimethylsilyl)oxy]cyclopentane(34)

To a suspension of magnesium (1.18 g, 48.5 mmol) in THF (15 mL) at roomtemperature in 100 mL round bottomed flask was added(chloromethyl)dimethylphenylsilane (8.86 g, 48.5 mmol). The resultingmixture was stirred for ˜1 hour to form the Grignard reagent. To thissolution, copper (I) bromide-dimethylsulfide complex (2.13 g, 10.4 mmol)was added, and the mixture was stirred at room temperature for 30minutes. The resulting solution was cooled to −78° C., and to it wasadded slowly chlorotrimethylsilane (1.2 g, 11.3 mmol), followed by asolution of 33 (2 g, 9.4 mmol) in THF (2 mL). The reaction mixture wasstirred at −78° C. for 1 hour and at 0° C. for 3 hours to complete thereaction. The reaction mixture was poured into a flask containinghexanes (200 mL) and stirred for 10 minutes. The mixture was filteredthrough a bed of diatomaceous earth (Celite®) and the resulting filtratewas concentrated in vacuo to dryness to afford the crude title compound.

PREPARATION OF[3S-(3α,4β)]-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-3-[(dimethylphenylsilyl)methyl]-2-(hydroxymethyl)cyclopentanone(35)

The residue containing 34 was dissolved in THF (80 mL) and transferredto a 500-mL round bottomed flask. To this solution was added yttriumtrifluoromethanesulfonate (5.84 g) and aqueous formaldehyde (18.5 mL, 37wt. % solution). The resulting mixture was stirred at room temperaturefor 12 hours to complete the reaction. The reaction was quenched by slowaddition of water (30 mL) and extracted with ethyl acetate (2×50 mL).The combined organic layer was washed with brine (200 mL), dried overmagnesium sulfate, and concentrated in vacuo to dryness to give thecrude title compound (2.12 g, 57% yield).

PREPARATION OF(3S,4S)-4-[(1,1-Dimethylethyl)dimethylsilyl]oxy]-3-[(dimethylphenylsilyl)methyl]-2-methylenecyclopentanone(36)

To a solution of 35 (1.2 g, 3.06 mmol) in DCM (20 mL) was addedtriethylamine (0.554 mL, 3.97 mmol) at −0° C. slowly followed bymethanesulfonyl chloride (0.284 mL, 3.67 mmol). The resulting mixturewas stirred for 2 hours at room temperature to complete the reaction andform the mesylate. 1,8-diazabicyclo[5.4.0]undec-7-ene (0.685 mL, 4.58mmol) was added to the reaction mixture and the reaction mixture wasstirred for 3 hours at room temperature to complete the reaction. Thereaction mixture was poured into a stirring mixture containing aqueousammonium chloride solution (10%, 25 mL) and DCM (25 mL). The organiclayer was separated and washed with water, brine, and dried overmagnesium sulfate. Concentration of the organic layer in vacuo gave thecrude title compound, 1.1 g in 96% yield.

PREPARATION OF[1R-(1α,3β,4α)]-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-3-[(dimethylphenylsilyl)methyl]-2-methylenecyclopentanol(37)

To a cooled (−78° C.), stirred solution of 36 (4.8 g, 12.81 mmol) in THF(25 mL) in a 100-mL round bottomed flask equipped with an argon inletwas added lithium triethylborohydride (super hydride®, 24.4 mL, 24.4mmol, 1.0 M THF solution) over a period of 15 minutes. The reactionmixture was stirred at the same temperature for 1 hour and slowly warmedto room temperature to complete the reaction. The reaction mixture wasquenched with sodium hydroxide solution (10%, 25 mL) and extracted withethyl acetate (2×25 mL). The organic layer was separated, washed withbrine (50 mL), and dried over magnesium sulfate. Concentration of theorganic layer in vacuo gave the crude title compound, 4.58 g in 95%yield in a 8:1 diastereomeric ratio. The title compound was purified byusing silica gel flash chromatography ethyl acetate/hexanes (1:4 v/v) toafford the desired diastereomer, 4 g in 83% yield.

PREPARATION OF[1S-(1α,3α,4β)]-9-[4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-3-[(dimethylphenylsilyl)methyl]-2-methylenecyclopentyl]-6-iodo-9H-purin-2-amine(38, X=I)

To a solution of 37 (1.6 g, 4.24 mmol) in THF (20 mL) in a 100-mL roundbottomed flask was added sequentially triphenylphosphine (1.49 g, 5.7mmol), iodo guanine (1.49 g, 5.7 mmol) and diethylazodicarboxylate (0.91mL, 5.7 mmol) at −78° C. The reaction mixture was stirred at −78° C. for2 hours, then warmed slowly to room temperature over a period of 1 hour,and stirred at room temperature for 12 hours to complete the reaction.The reaction was quenched by addition of saturated ammonium chloridesolution (50 mL) and the resulting mixture extracted with a mixture oftert-butyl methyl ether and heptane (1:4; 2×25 mL). The organic layerwas dried over magnesium sulfate and concentrated in vacuo to give crudeproduct which was purified by silica gel chromatography to afford thetitle compound in 71% yield (1.87 g).

PREPARATION OF[1R-(1α,3α,5β)]-3-(2-Amino-6-iodo-9H-purin-9-yl)-5-hydroxy-2-methylenecyclopentanemethanol(39)

To a solution of 38 (1.8 g, 2.9 mmol) in DCM (25 mL) was addedtetrafluoroboric acid-dimethyl ether complex (3.53 mL, 29 mmol) at roomtemperature. The resulting mixture was stirred for 4 hours. MeOH (25 mL)was added to the reaction mixture to make it homogenous. Solid potassiumbicarbonate (4.35 g, 43.5 mmol) was slowly added and the resultingmixture stirred at room temperature for 1.5 hours. Potassium fluoride(0.85 g, 14.6 mmol) was added, followed by aqueous hydrogen peroxide (30wt. % solution, 3 mL). The reaction mixture was stirred at roomtemperature for 4 hours. The reaction mixture was concentrated in vacuoto dryness to give a residue. The residue was triturated with DCM (3×25mL). The combined organic layer was concentrated in vacuo to give thetitle compound as a solid (0.96 g, 85% yield).

PREPARATION OF[1S-(1α,3α,4β)]-1,9-Dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one(21)

A mixture of 39 (0.5 g, 1.29 mmol) in sodium hydroxide (2 N, 10 mL) washeated at 70° C. under an atmosphere of argon for 1 hour to complete thereaction. The reaction mixture was cooled to 0° C. and neutralizedslowly by addition of 3 N HCl. Decolorizing carbon (0.5 g) was added.This mixture was heated at ˜90° C. for 1 hour. The hot mixture wasfiltered through a bed of diatomaceous earth (Celite®). The resultingclear filtrate was cooled and seeded with 21 to effect crystallization.The product was collected by filtration and dried under vacuum to affordthe title compound as a white crystalline solid (0.21 g, 60% yield).

EXAMPLE 12 PROCESS FOR THE PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one(21) PREPARATION OF(1R,4S)-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-2-iodo-2-cyclopenten-1-ol(40)

To a solution of 33 (40 g, 188 mmol, as prepared in Example 11) in THF(100 mL) in 1-L round bottomed flask was added a solution of iodine (105g, 414 mmol) in DCM (100 mL). The resulting solution was stirred at 0°C. To this solution, pyridine (36 mL) was slowly added through adropping funnel over a period of 20 minutes. The mixture was thenstirred at the same temperature for 3 hours to complete the reaction.The reaction mixture was diluted with tert-butyl methyl ether (300 mL)and washed with sodium bisulfite solution (600 mL), HCl (0.5 N, 500 mL),brine (200 mL) and dried over magnesium sulfate. The organic layer wasconcentrated in vacuo to dryness to give the intermediate iodo-ketone asa yellow oil (56 g) in 89% yield.

To a round bottomed flask equipped with an argon inlet, magnetic stirrerwas charged cerium chloride heptahydrate (30.8 g, 82.75 mmol) and MeOH(150 mL) and stirred at room temperature for 30 minutes. To this stirredsolution, the iodo-ketone (56 g, 165.5 mmol) in MeOH (60 mL) was addedand cooled to −60° C. To this cooled solution, sodium borohydride (6.25g, 165.5 mmol) was added in portion-wise. After stirring the reactionmixture at −50° C. for 20 minutes, the reaction was warmed to −30° C.and stirred for another 30 minutes to complete the reaction as judged byTLC. The reaction mixture was diluted with tert-butyl methyl ether (400mL) and washed with saturated sodium bicarbonate and brine. The organiclayer was dried over magnesium sulfate and filtered on a sinteredfunnel. The filtrate was concentrated on a rotary evaporator to affordthe desired product 40 as yellow oil (51 g, 91% yield).

PREPARATION OF(3S,5R)-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-hydroxy-1-cyclopentene-1-carboxylicacid methyl ester (41)

To a solution of 40 (18 g, 52.89 mmol) in MeOH (100 mL) in a sealedreactor (Parr reactor) was added triethylamine (36 mL, 264.5 mmol) anddichlorobis(triphenylphosphine)palladium II [PdCl₂(Ph₃P)₂] (2 mole %).The reactor was flushed with nitrogen for about 5 minutes. The reactorwas heated to about 50° C. and pressurized to about 15 psi. The reactionwas continued while stirring at the same pressure and temperature for 5hours to complete the reaction. The reaction mixture was concentrated,diluted with ethyl acetate (50 mL) and filtered. The organic layer waswashed with water, brine and dried over magnesium sulfate. The organiclayer was concentrated in vacuo to dryness to give crude product whichwas purified by column chromatography to give the title compound (11.6g) in ˜81% yield.

PREPARATION OF (3S,5R)-5-(Benzoyloxy)-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-cyclopentene-1-carboxylic acid methyl ester (42)

To a solution of 41 (0.55 g, 2 mmol) in THF (2 mL) at −78° C. was addedlithium hexamethyldisilazide (3 mL, 1 M, 3 mmol) and the resultingsolution was stirred for 1 hour. To this solution, 1-adamantanecarbonylchloride (596 mg, 3 mmol) was added and the resulting mixture wasstirred for 15 min at −78° C. followed by 30 minutes at room temperatureto complete the reaction. The reaction mixture was diluted with ethylacetate (25 mL) and washed with sodium bicarbonate solution, water, andbrine. The organic layer was concentrated in vacuo to dryness to givethe crude product. The crude product was crystallized from MeOH-water togive the title compound (0.57 g) in ˜75% yield.

PREPARATION OF(4S,5S)-4-[[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-[(dimethylphenylsilyl)methyl]-1-cyclopentene-1-carboxylicacid methyl ester (43)

To a suspension of magnesium (1.18 g, 48.5 mmol) in THF (15 mL) at roomtemperature was added phenyldimethylchlorosilane (8.86 g, 48.5 mmol).The resulting mixture was stirred for ˜1 hour to form the Grignardreagent. To this solution, copper (I) iodide (0.3 g, 5%) was added andthe resulting solution stirred at room temperature for 30 minutes. Theresulting solution was cooled to −78° C. and to it was added slowly asolution of 42 (14 g, 32.33 mmol) in THF (20 mL). The reaction mixturewas stirred at −78° C. for 7 hours to complete the reaction. Thereaction was quenched by slow addition of MeOH (10 mL) and warming toroom temperature. The mixture was diluted with ethyl acetate (300 mL)and washed with saturated ammonium chloride (200 mL), sodium hydroxide(1 N, 2×150 mL), water (100 mL) and brine (100 mL). The organic layerwas dried over magnesium sulfate and concentrated in vacuo to give thecrude title compound, 13 g in 100% yield.

PREPARATION OF(4S,5S)-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-[(dimethylphenylsilyl)methyl]-1-cyclopentene-1-methanol(44)

To a solution of 43 (15 g, 37.13 mmol) in hexanes (100 mL) was addeddiisobutylaluminum hydride (113 mL, 113.4 mmol, 1 N in hexanes) at −78°C. slowly over a period of 30 minutes keeping the temperature below −60°C. The resulting mixture was stirred for 2 hours at the same temperatureto complete the reaction. The reaction mixture was quenched by additionof sodium hydroxide (2 N, 200 mL). The organic layer was separated andwashed with water, brine, and dried over magnesium sulfate. The organiclayer was concentrated in vacuo to dryness to give the crude titlecompound (13 g, 100% yield).

PREPARATION OF(1R,2R,3S,5R)-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-2-[(dimethylphenylsilyl)methyl]-6-oxabicyclo[3.1.0]hexane-1-methanol(45)

To a cooled (0° C.), stirred solution of 44 (14 g, 37.23 mmol) in MeOH(50 mL) was added magnesium monoperoxyphthalate (MPPA, 80% pure, 27.62g, 44.68 mmol) in six portions over a period of 1 hour, keeping thetemperature <0° C. The reaction mixture was stirred at the sametemperature for 4 hours to complete the reaction. The reaction mixturewas diluted with ethyl acetate (300 mL) and washed with saturated sodiumbisulfite (200 mL), sodium hydroxide (0.5 N, 2×150 mL), brine (150 mL)and dried over magnesium sulfate. The organic layer was concentrated invacuo to dryness to give the crude title compound (13.5 g, 92%)

PREPARATION OF[1S-(1α,2β,3α,5β)]-5-[2-Amino-6-(benzoyloxy)-9H-purin-9-yl]-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-2-[(dimethylphenylsilyl)methyl]-1-hydroxycyclopentanemethanol(46, X=BnO)

To a solution of 2-amino-6-O-benzyloxypurine (20 g, 84 mmol) indimethylformamide (50 mL) at room temperature was added lithium hydride(0.4 g, 50.4 mmol) as a solid in one portion. The suspension was stirredat room temperature for 4 hours at which point a clear solution wasobserved. To this solution was added a solution of 45 (13.2 g, 33.6mmol) in dimethylformamide (20 mL). The reaction mixture was heated at80° C. for 4 hours to complete the reaction. The reaction mixture wasdiluted with ethyl acetate (200 mL) and washed with sodium hydroxide (1N, 200 mL), water (100 mL) and brine (100 mL). The organic layer wasstirred with charcoal (20 g) for 1 hour and filtered. The filtrate wasconcentrated in vacuo to dryness to give crude product (20.4 g). Thecrude product was crystallized from MeOH to give the title compound aswhite solid (8.8 g, 41% yield).

PREPARATION OF [1S-(1α,3α,4β)]-2-amino-9-[4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-[(dimethylphenylsilyl)methyl]-2-methylenecyclopentyl]-9H-purin-6-one(47)

To a round bottomed flask equipped with a magnetic stirrer and nitrogeninlet/outlet was charged compound 46 (1.27 g, 2 mmol),trimethylorthoformate (2.12 g, 20 mmol) and CH₂Cl₂ at room temperature.The reaction mixture was cooled to 0° C. and pyridiniump-toluenesulfonate (5 mg) was added to the solution. The reactionmixture was warmed to room temperature and stirred overnight. Thereaction mixture was concentrated in vacuo to dryness, and the resultingconcentrate extracted with ethyl acetate (100 mL) and saturated NaHCO₃solution (50 mL). The organic layer was separated, dried (Na₂SO₄), andconcentrated in vacuo to afford thick light yellow oil. The oil wasmixed with excess acetic anhydride (25 mL) and a catalytic amount ofacetic acid (2 drops), and the resulting mixture was heated to refluxfor 10 h. After cooling to room temperature, the excess acetic anhydridewas removed by vacuum distillation, and the resulting brown oil wasmixed with MeOH (30 mL) and 4 N HCl solution (10 mL). The solution washeated to reflux under a nitrogen atmosphere overnight. The MeOH wasremoved by distillation and the solution was neutralized to a pH of ˜7.2with NaOH (10 N, ˜4.5 mL). The resulting suspension was extracted withCH₂Cl₂ (2×100 mL). The combined organic layer was dried (Na₂SO₄) andconcentrated in vacuo to afford a thick semi-solid oil (compound 47).The crude compound 47 could be used in the next reaction without furtherpurification.

PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one(21)

To a solution of compound 47 (1 g, 1.67 mmol) in DCM (10 mL) was addedtetrafluoroboric acid-dimethyl ether complex (0.45 g, 3.34 mmol) at 0°C. The solution was stirred for 2 hours at 0° C. followed by 14 hours atroom temperature. To this solution was added sequentially, potassiumbicarbonate (10 g, 10 mmol), potassium fluoride (0.58 g, 10 mmol), andaqueous hydrogen peroxide (30 wt. % solution, 1.2 mL, 10.6 mmol). Thereaction mixture was stirred at room temperature for 14 hours. Thereaction mixture was concentrated in vacuo. The residue wasrecrystallized from water to afford the title compound (180 mg, 39%yield).

EXAMPLE 13 PROCESS FOR THE PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one(21) PREPARATION OF[3aS-(3aα,4α,5β,6aα)]-5-(Acetyloxy)-4-[(acetyloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-one(50)

To a 100 mL round bottomed flask was charged(3aS,6aR)-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]furan-2-one 49 (3.85 g,31 mmol, prepared as described in Corey et al. J. Med Chem. 1993, 36,243), paraformaldehyde (3.0 g), glacial acetic acid (30 mL), andconcentrated sulfuric acid (1 mL). The mixture was heated to 74° C. for24 hours. To the solution was added sodium acetate (4 g). The solutionwas concentrated in vacuo and the residue was dissolved in ethyl acetate(200 mL). The solution was washed with saturated sodium bicarbonatesolution until no gas evolution was observed. The organic phase wasdried over sodium sulfate and concentrated in vacuo to give the crudeproduct (4.1 g). The crude product was purified by silica gel columnchromatography to provide the title compound (3.1 g, 39%).

PREPARATION OF[3aS-(3aα,4α,5β,6aα)]-Hexahydro-5-hydroxy-4-(hydroxymethyl)-2H-cyclopenta[b]furan-2-one(51)

To a solution of 50 (10.0 g, 39 mmol) in MeOH (100 mL) was addedpotassium carbonate (15 g). The suspension was stirred at roomtemperature for 3 hours. To the suspension was added ethyl acetate (60mL). The resulting suspension was filtered through a pad of diatomaceousearth (Celite®). The filtrate was concentrated in vacuo to give crudeproduct. The crude product was dissolved in MeOH (15 mL) and to it wasadded diethyl ether (100 mL). The resulting suspension was stirred for 2hours at room temperature. The solid was filtered to give the titlecompound (3.62 g, 54%).

PREPARATION OF (3aS-(3aα,4α,5β,6aα)]-5-[((1,1-Dimethylethyl)dimethylsilyl]oxy]-4-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]hexahydro-2H-cyclopenta[b]furan-2-one(52)

To a suspension of 51 (4.1 g, 23.8 mmol) in DCM (40 mL) was addedN,N-diisopropylethylamine (9.44 g, 71.4 mmol),4-N,N-dimethylaminopyridine (0.41 g), and tert-butyldimethylsilylchloride (10.8 g, 71.4 mmol). The reaction mixture was stirred at roomtemperature for 14 hours. The reaction was worked up by washing with 1.0N HCl, 1.0 N sodium hydroxide, and brine. The organic solution wasconcentrated in vacuo to give the crude product. Column chromatographyon silica gel using ethyl acetate/hexanes (1/2 v/v) to give the titlecompound (7.8 g, 82%).

PREPARATION OF [1R-(1α,2β,3α,5α)]-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-2-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]-5-hydroxycyclopentanemethanol(54)

To a suspension of 52 (1.0 g, 2.5 mmol) and(1S)-(+)-(10-camphorsulfonyl) oxaziridine (0.86 g, 7.75 mmol) in THF (10mL) was added sodium hexamethyldisilazide (5 mL of 1 M solution in THF)at −78° C. The reaction mixture was stirred for 1.5 hours. It was thenquenched with MeOH (15 mL) at −78° C. and to the mixture was addedsodium borohydride, (0.34 g, 9.0 mmol). The reaction mixture was warmedto room temperature and stirred for 1 hour. It was poured into ethylacetate (100 mL), washed with 1.0 N sodium hydroxide (3×50 mL), driedover sodium sulfate, and concentrated in vacuo to give the crude triolintermediate 53A (1.1 g). The intermediate 53A was dissolved in MeOH (10mL) and water (5 mL). To the resulting solution was added sodiumperiodate (2.14 g, 10.0 mmol) and the resulting mixture was stirred for1 hour at room temperature. The mixture was poured into ethyl acetate(100 mL), washed with water (50 mL), dried over sodium sulfate, andconcentrated in vacuo to give the crude aldehyde intermediate 53B. Theresidue was dissolved in MeOH (10 mL), and to it was added sodiumborohydride (0.227 g, 6.0 mmol) at 0° C. The reaction mixture wasstirred for 1 hour. Column purification of the crude product on silicagel using ethyl acetate/hexanes (1/2 v/v) gave the title compound (0.68g, 70%).

PREPARATION OF [1R-(1α,2α,3α,4α)]-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-3-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]-2-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-cyclopentanolacetate ester (55)

To a solution of 54 (0.7 g, 1.79 mmol) in DCM (3 mL) was added pyridine(1 mL), and p-toluenesulfonyl chloride (0.34 g, 1.79 mmol) at 0° C. Thereaction mixture was warmed to room temperature and stirred for 20hours. To the reaction mixture was added pyridine (1 mL), and aceticanhydride (1 mL) at room temperature. The reaction mixture was stirredfor 18 hours. It was poured into ethyl acetate (50 mL), washed with 1.0N sodium hydroxide (2×20 mL), brine (20 mL), dried over sodium sulfate,and concentrated in vacuo to afford the title compound (0.86 g, 77%).

PREPARATION OF[1R-(1α,3β,4α)]-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-3-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]-2-methylenecyclopentanol(56)

To a solution of 55 (0.585 g, 0.88 mmol) in dimethylformamide (4 mL) wasadded lithium iodide (0.236 g, 1.76 mmol), and1,8-diazabicyclo[5.4.0]undec-7-ene (10 eq). The resulting mixture washeated to 100° C. for 2 hours. The mixture was cooled to roomtemperature and to it was added MeOH (4 mL). The mixture was stirred for14 hours at room temperature. It was poured into ethyl acetate (100 mL),washed with 1.0 N HCl (3×20 mL), brine (20 mL), dried over sodiumsulfate, and concentrated in vacuo. Purification via silica gelchromatography using ethyl acetate/hexanes (1:2, v/v) gave the titlecompound (0.18 g, 52%).

PREPARATION OF [1S-(1α,3α,4β)]-6-Chloro-9-[4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]-2-methylenecyclolpentyl]-9H-purin-2-amine(57)

To a suspension of 56 (120 mg, 0.32 mmol), triphenylphosphine (84.5 mg,0.64 mmol), and 2-amino-6-chloropurine (108 mg, 0.64 mmol) in THF (10mL) was added diethyl azodicarboxylate (111 mg, 0.64 mmol) at −20° C.The reaction mixture was stirred at −20° C. for 1 hour. It was pouredinto DCM (50 mL), washed with 0.5 N sodium hydroxide (3×10 mL), driedover sodium sulfate, and concentrated in vacuo. Purification via silicagel chromatography gave the title compound (0.11 g, 63%).

PREPARATION OF[1S-(1α,3α,4β)]-6-Chloro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-9H-purin-2-amine(39)

To a solution of 57 (180 mg, 0.344 mmol) in THF (2 mL) was addedtetrabutylammonium fluoride (2 mL of 1 M solution in THF). The reactionmixture was stirred at room temperature for 1 hour. It was poured intoDCM (50 mL), washed with water (3×10 mL), dried over sodium sulfate, andconcentrated in vacuo to give the title compound (55 mg, 54%).

PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one(21)

39 was converted to 21 by the procedure described in Example 11.

EXAMPLE 14 PROCESS FOR THE PREPARATION OF[1S-(1α,3α,4β)]-2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one(21) PREPARATION OF(2-Benzyloxymethyl-6-oxa-bicyclo[3.1.0]hex-3-yloxy)-tert-butyl-dimethylsilane(83) (R^(c)=tert-butyl, R^(d)=CH₃)

A solution of t-butyldimethyl chlorosilane (3.58 g, 23.8 mmol) in DMF(10 mL) was slowly added to a solution of DMAP (0.25 g, 2.0 mmol),imidazole (3.24 g, 48 mmol), and2-benyloxy-6-oxa-bicyclo[3.1.0]hexan-3-ol 82 (3.5 g, 15.9 mmol) in DMF(20 mL) at room temperature. The mixture was stirred at room temperaturefor 16 h. The reaction was quenched with water (50 mL) and extractedwith ethyl acetate-hexane (1:1, 180 mL). The organic layer wasseparated, washed with water (80 mL) and half saturated brine (80 mL),and dried (Na₂SO₄). Concentration followed by purification with silicagel chromatography gave 4.85 g (91%) of desired product 83 as an oil.

PREPARATION OF[3-(tert-Butyl-dimethyl-silanyloxy)-6-oxa-bicyclo[3.1.0]hex-2-yl]-methanol(84) (R^(c)=tert-butyl, R^(d)=CH₃)

A mixture of ether 83 (2.0 g), and 10% Pd/C (0.5 g) in MeOH (45 mL) wasstirred at room temperature under hydrogen (1 atm) for 3.5 h. Themixture was treated with ethyl acetate (60 mL) for 10 min. The catalystwas removed by filtration on diatomaceous earth (Celite®) and washedwith ethyl acetate (40 mL). Concentration of the filtrate under vacuumfollowed by purification of the product on a silica gel pad provided1.39 g (95%) of alcohol 84 as an oil.

PREPARATION OF Toluene-4-sulfonic acid3-(tert-butyl-dimethyl-silanyloxy)-6-oxa-bicyclo[3.1.0]hex-2-ylmethylester (85) (R^(c)=tert-butyl, R^(d)=CH, R³=p-methylphenyl)

A solution of p-toluenesulfonyl chloride (1.12 g, 5.9 mmol) in DCM (10mL) was slowly added to a solution of alcohol 84, triethylamine (2.1 g,21 mmol), and DMAP (0.12 g, 1.0 mmol) in DCM (25 mL) at roomtemperature. The mixture was stirred at room temperature for 16 h,treated with hexane (60 mL), washed with water (25 mL×3) and brine (20mL), and dried (Na₂SO₄). Concentration of the solution followed bypurification with silica gel chromatography gave 1.91 g (96%) oftosylate 85 as a white solid.

PREPARATION OFtert-Butyl-dimethyl-(2-methylen-6-oxa-bicyclo[3.1.0]hex-3-yloxy)-silane(86) (R^(c)=tert-butyl, R^(d)=CH₃)

Potassium t-butoxide (1.9 g, 15.6 mmol) was added to a solution oftosylate 85 (5.2 g, 13.0 mmol) in THF (100 mL) at 0° C. After stirringat 0° C. for 1.5 h, the mixture was treated with hexane (200 mL), washedwith water (100 mL×2) and brine (80 mL×2), dried (Na₂SO₄). Concentrationof the solution gave 2.75 g (93%) of alkene 86 as an oil.

PREPARATION OF4-(tert-Butyl-dimethyl-silanyloxy)-2-[1,3]dithian-2-yl-3-methylene-cyclopentanol(87) (R^(c)=tert-butyl, R^(d)=CH₃)

A butyllithium solution (2.5 M in hexane, 4.8 mL, 12 mmol) was added toa solution of 1,3-dithiane (1.5 g, 12 mmol) in THF (22 mL) at 0° C.under nitrogen. The mixture was stirred at room temperature for 1 h andthen cooled to 0° C. The above solution was slowly added to a solutionof vinylepoxide 86 (2.3 g, 10 mmol) in THF (40 mL) at −30° C. Themixture was stirred at −30° C. for 3 h and then warmed up to roomtemperature. The reaction was quenched by addition of hexane (80 mL) and5% aqueous KH₂PO₄ solution (70 mL). The organic layer was separated,washed with brine (60 mL×2), and dried (Na₂SO₄). Concentration of thesolution followed by purification with silica gel chromatography gave3.06 g (88%) of dithiane 87 as a white solid.

PREPARATION OF4-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxymethyl-3-methylene-cyclopentanol(88) (R^(c)=tert-butyl R^(d)=CH₃)

A mixture of dithiane 87 (0.60 g, 1.7 mmol), calcium carbonate (1.3 g,13 mmol), and iodomethane (2.4 g, 16.4 mmol) in acetonitrile-water(94:6, 8 mL) was stirred at room temperature for 16 h. Ethyl acetate (10mL) and hexane (10 mL) were added to the reaction mixture which was thendried over sodium sulfate. The solid was removed by filtration.Concentration of the filtrate provided a crude aldehyde which was thendissolved in ethanol and cooled to 0° C. Sodium borohydride (120 mg, 3.2mmol) was added at 0 0° C. The mixture was stirred at 0° C. for 1 h. Thereaction was quenched with a saturated aqueous KH₂PO₄ solution (5 mL)and water (5 mL). Ethanol was removed by evaporation under vacuum. Theaqueous layer was extracted with ethyl acetate (15 mL×2). The combinedorganic layers were dried (Na₂SO₄). Concentration of the solutionfollowed by purification with silica gel chromatography gave 301 mg(67%) of the diol 88.

PREPARATION OF Acetic acid2-acetoxymethyl-4-hydroxy-3-methylene-cyclopentyl ester (89) (R²=CH₃)

Acetic anhydride (250 mg, 2.5 mmol) was added to a mixture of diol 88,DMAP (10 mg, 0.08 mmol), and triethylamine (360 mg, 3.6 mmol) in DCM (5mL) under nitrogen at room temperature. After 3 h at room temperature,the reaction mixture was treated with hexane (10 mL), ethyl acetate (5mL), and half saturated brine (10 mL). The organic layer was separated,washed with half saturated brine (10 mL), and dried (Na₂SO₄).Concentration of the solution gave a crude bis-acetate which wasdissolved in THF (10 mL). Tetrabutylammonium fluoride (TBAF.3H₂O, 400mg, 1.3 mmol) was added to the solution at room temperature. After 1 h,the reaction mixture was treated with ethyl acetate (20 mL) and thenwashed with brine (15 mL×2). The aqueous layers were back-extracted withethyl acetate (15 mL). The combined organic layers were dried (Na₂SO₄).Concentration of the solution followed by purification with silica gelchromatography gave 255 mg (96%) of the desired alcohol 89 as an oil.

PREPARATION OF Acetic acid2-acetoxymethyl-4-(2-amino-6-iodopurin-9-yl)-3-methylene-cyclopentylester (90) (R²=CH₃, X=I)

A mixture of alcohol 89 (106 mg, 0.44 mmol), triphenylphosphine (137 mg,0.52 mmol), and 6-iodo-2-aminopurine (115 mg, 0.44 mmol) in THF wascooled to 0° C. DEAD (87 mg, 0.50 mmol) was slowly added to the mixturewhich was stirred at 0° C. for 3 h and then warmed up to roomtemperature for 16 h. The mixture was treated with ethyl acetate (9 mL)and filtered on diatomaceous earth (Celite®). Concentration of thefiltrate provided a residue which was treated with ethyl acetate (3 mL),2 N HCl (4 mL), and hexane (6 mL). The aqueous layer was separated. Theorganic layer was extracted with 2 N HCl (4 mL×3). The combined aqueouslayers was neutralized with K₂HPO₄ to pH ˜7 and extracted with ethylacetate (25 mL, 10 mL). The combined organic layers were dried (Na₂SO₄)and concentrated to give a crude product which was purified by silicagel chromatography to provide 175 mg (85%) of 90 containing sometriphenylphosphine oxide. Crystallization of the crude product fromethanol gave 132 mg (64%) of desired 90.

The compound of formula 90 can be converted to the compound of formula21 by hydrolysis of the ester group using, for example, by treatmentwith an alkali metal alkoxide. The 6-iodo group can be hydrolyzed toprovide the compound of formula 21, according to the procedure describedfor the preparation of compound of formula 21 in Example 11.

Where noted above, publications and references, including but notlimited to patents and patent applications, cited in this specificationare herein incorporated by reference in their entirety in the entireportion cited as if each individual publication or reference werespecifically and individually indicated to be incorporated by referenceherein as being fully set forth.

While this invention has been described with an emphasis upon preferredembodiments, it will be obvious to those of ordinary skill in the artthat variations in the preferred devices and methods may be used andthat it is intended that the invention may be practiced otherwise thanas specifically described herein. Accordingly, this invention includesall modifications encompassed within the spirit and scope of theinvention as defined by the claims that follow. For example, it shouldbe understood that the reaction steps set forth in the appended claimsneed not necessarily be performed in the order in which they appear, andone skilled in the field may be able to vary the order of reactionsteps. Additionally, certain reaction sequences may be performedsimultaneously, such as, for example, protodesilylation anddebenzylation, or these reactions can be performed in separate steps,without departing from the spirit and scope of the invention. It isintended that all such modifications are encompassed within the scope ofthe appended claims.

1. A process for the preparation of entecavir having the formula

(a) treating an ester of the formula

wherein R^(a) is allyl, phenyl, C₁ to C₆ alkylphenyl, or C₁ to C₆alkoxyphenyl; R^(b) is C₁ to C₆ alkyl; and R is C₁ to C₄ alkyl orbenzyl; with an enol ether of acetone and an acid to protect the hydroxygroup, followed by treatment with a hydride reagent to reduce thecarboxylic acid ester moiety, and then alkylating the resulting alcoholwith a benzyl halide and removing the enol ether hydroxy protectinggroup to give an allylic alcohol of the formula

(b) epoxidizing the product from step (a) with a diastereoselectiveepoxidation to give a cyclopentane epoxide having the formula

(c) treating the cyclopentane epoxide from step (b) with an alkali metalsalt of a purine compound of formula

wherein X is Cl, I, or benzyloxy, to give a compound of formula

(d) when X is Cl or I, converting the vicinal diol of formula 78 to themethylene compound of formula,

(e) hydrolyzing the benzyl ether moiety on the primary alcohol ofcompound 94 and converting the silane moiety of compound 95 to a hydroxymoiety to give a compound of formula,

(f) hydrolyzing the chloro or iodo moiety X to provide the compound offormula 21; or (d′) when X is benzyloxy, converting the vicinal diol offormula 78 to the methylene compound of formula

(e′) hydrolyzing the benzyl ether moiety on the primary alcohol ofcompound 79 and converting the silane moiety to a hydroxy moiety toprovide the compound of formula 21; or (a″) epoxidizing the ester offormula 66 with a diastereoselective expoxidation, to give acyclopentane epoxide having the formul

(b″) treating the cyclopentane epoxide from step (a″) with an alkalimetal salt of the purine compound of formula 28 to give a compound offormula

(c″) when X is Cl or I, converting the vicinal diol of formula 73 to themethylene compound of formula

(d″) converting the silane moiety of compound 92 to a hydroxy moiety andhydrolyzing the chloro or iodo moiety X to provide the compound offormula 21; or (c′″) when X is benzyloxy, converting the vicinal diol offormula 73 to the methylene compound of formula

(d′″) converting the silane moiety of compound 71 to a hydroxy moiety toprovide the compound of formula
 21. 2. The process of claim 1, in which,in steps (b) and (a″), the diastereoselective epoxidation is performedwith a peracid or with a homochiral diester of tartaric acid, ahydroperoxide, and a metal catalyst.
 3. A process for the preparation ofentecavir having the formula

(a) protecting the hydroxy moiety of an ester of the formula

wherein R^(a) is allyl, phenyl, C₁ to C₆ alkylphenyl, or C₁ to C₆alkoxyphenyl; R^(b) is C₁ to C₆ alkyl; and R is C₁ to C₄ alkyl orbenzyl, to provide a compound of formula

wherein P′ is a protecting group; (b) reducing the carboxylic estermoiety of the compound 74′ with at least one reducing reagent to providea compound of formula,

(c) protecting the unprotected hydroxy moiety of compound 75′, with aprotecting group P″ that is resistant to conditions used to remove P′,then removing the protecting group P′ of the compound of 75′, to providethe compound having the formula,

(d) epoxidizing the product from step (c) with a diastereoselectiveepoxidation to give a cyclopentane epoxide having the formula

(e) treating the cyclopentane epoxide from step (d) with an alkali metalsalt of a purine compound of formula

wherein X is Cl, I, or benzyloxy; to give a compound of formula

(f) when X is benzyloxy, converting the vicinal diol of formula 78′ toprovide the methylene compound of formula

(g) removing the protecting group P″ on the primary alcohol of compound79 and converting the silane moiety to a hydroxy moiety to provide thecompound of formula 21; or (f′) when X is Cl or I, converting thevicinal diol of formula 78′ to provide the methylene compound offormula,

(g′) removing the protecting group P″ on the primary alcohol of compound94′ and converting the silane moiety to a hydroxy group to give acompound of formula,

(h′) hydrolyzing the chloro or iodo moiety X to provide the compound offormula
 21. 4. The process of claim 3, wherein, in step (g), theprotecting group P″ on the primary alcohol of compound 79′ is benzyl,said step of converting the silane moiety of compound 79 to a hydroxygroup is achieved with protodesilylation and oxidation, and said benzylprotecting group is removed upon protodesilylation.
 5. The process ofclaim 3, wherein the protecting group P″ on the primary alcohol ofcompound 79′ is removed after the silane moiety is converted to ahydroxy moiety.
 6. The process of claim 3, wherein in step (a), thehydroxy moiety is protected as a MOP by treatment with 2-methoxypropeneand a catalytic amount of a weak acid.
 7. The process of claim 3,wherein in step (b), the carboxylic ester moiety of the compound 74′ isreduced with a hydride reagent selected from at least one of sodiumbis(2-methoxyethoxy)aluminum hydride and lithium aluminum hydride in thepresence of a base.
 8. The process of claim 3, wherein in step (c), theunprotected hydroxy moiety is protected as a benzyl ether upon treatmentwith a base and a benzyl halide, wherein, removal of the protectinggroup P′ of the compound of 75′ provides the allylic alcohol having theformula,


9. The process of claim 8, wherein the base is selected from at leastone of potassium tert-butoxide, sodium hydride, KHMDS, and aqueous NaOH,and the benzyl halide is benzyl bromide or benzyl chloride.
 10. Theprocess of claim 3, in which in step (d), the diastereoselectiveepoxidiation is performed by treatment with a peracid.
 11. The processof claim 3, in which in step (d), the diastereoselective epoxidiation isperformed by treatment with a homochiral diester of tartaric acid, ahydroperoxide, and a metal catalyst
 12. The process of claim 11, whereinthe homochiral diester of tartaric acid is (−)-diisopropyl tartrate, thehydroperoxide is tert-butylhydroperoxide orα,α-dimethylbenzylhydroperoxide, and the metal catalyst is titanium (IV)isopropoxide.
 13. The process of claim 3, wherein in step (e), thecyclopentane epoxide from step (d) is treated with2-amino-6-benzyloxypurine in dichloromethane.
 14. The process of claim3, wherein X is benzyloxy and in step (f), the compound 78′ is convertedto the methylene compound of formula 79′ by (f)(i) treating compound 78′with an orthoformate derivative in an inert solvent to produce adiastereomixture of dioxolanes having the formulae 101′ and 103′,

wherein R²² is C₁₋₄alkyl or —C(═O)C₁₋₄alkyl; (f)(ii) treating theproduct from step (f)(i) with an acetic anhydride in the presence of atleast one antioxidant to produce an alkene compound having the formula105′;

(f)(iii) treating the product from step (f)(ii) with an acid tohydrolyze the 6-benzyloxy and N-acetyl groups to provide the compound offormula 79′.
 15. The process of claim 14, wherein in step (f)(i), theorthoformate derivative is selected from at least one of diethoxymethylacetate, diisopropyloxymethyl acetate, TMOF, TEOF, and TiPOF.
 16. Theprocess of claim 14, wherein in step (f)(ii), at least one antioxidantis selected from BHT and benzoic acid.
 17. The process of claim 3, inwhich the step of converting the compound 79′ to compound 21 is achievedwith protodesilyation and oxidation, wherein the protodesilylation isperformed with KOH or NaOH in solvent, or with TFA, and the primaryalcohol moiety is deprotected after the silane moiety is converted to ahydroxy group, to provide the compound of formula
 21. 18. The process ofclaim 3, in which the step of converting the compound 79′ to compound 21is achieved with protodesilyation and oxidation, wherein the step ofprotodesilyation is achieved with at least one acid selected from borontrifluoride-acetic acid complex and a Bronsted acid.
 19. The process ofclaim 3, in which the step of converting the compound 79′ to compound 21is achieved with protodesilyation and oxidation, and the oxidation isachieved with hydrogen peroxide in the presence of potassium bicarbonateand optionally potassium fluoride.
 20. A process for the preparation ofentecavir having the formula

(a) treating an ester of the formula

wherein R^(a) is allyl, phenyl, C₁ to C₆ alkylphenyl, or C₁ to C₆alkoxyphenyl; R^(b) is C₁ to C₆ alkyl; and R is C₁ to C₄ alkyl orbenzyl; with 2-methoxypropene and a catalytic amount of a weak acid toprovide a compound of formula

(b) reducing the carboxylic ester moiety of the compound 74 with ahydride reagent selected from at least one of sodiumbis(2-methoxyethoxy)aluminum hydride and lithium aluminum hydride, inthe presence of a base to provide a compound of formula,

(c) protecting the unprotected hydroxy moiety of compound 75, as abenzyl ether upon treatment of compound 75 with a base and a benzylhalide, then removing the MOP group of the compound 75, to provide theallylic alcohol having the formula,

(d) epoxidizing the product from step (c) with (−)-diisopropyl tartrate,tert-butylhydroperoxide or cumene hydroperoxide, and titanium (IV)isopropoxide, to give a cyclopentane epoxide having the formula

(e) treating the cyclopentane epoxide from step (d) with an alkali metalsalt of a purine compound of formula

wherein X is benzyloxy; to give a compound of formula

(f))(i) treating compound 78 with an orthoformate derivative selectedfrom diethoxymethyl acetate and diisopropyloxymethyl acetate in an inertsolvent to produce a diastereomixture of dioxolanes having the formulae101 and 103,

wherein R²² is ethyl, —C(═O)ethyl, isopropyl, or —C(═O)isopropyl;(f)(ii) treating the product from step (f)(i) with an acetic anhydridein the presence of BHT to produce an alkene compound having the formula105;

(f)(iii) treating the product from step (f)(ii) with an acid tohydrolyze the 6-benzyloxy and N-acetyl groups and provide the compoundof formula 79,

(g) converting the silane moeity to a hydroxy moiety byprotodesilylating the silane moiety of compound 79 upon treatment withat least one reagent effective to achieve protodesilylation, followed byoxidation with a peroxide, and debenzylating compound 79 whereindebenzylation may be achieved upon protodesilylation, to provide thecompound of formula
 21. 21. The process of claim 20, in which step (g)comprises treating compound 79 with an acid selected from borontrifluoride-acetic acid complex and a Bronsted acid, wherein said stepof protodesilylation removes the benzyl protecting group of compound 79to provide the compound of formula 91,

oxidizing the compound 91 with hydrogen peroxide in the presence ofpotassium bicarbonate and potassium fluoride to provide the compound 21.22. The process of claim 20, in which step (g) comprises treatingcompound 79 with potassium hydroxide or sodium hydroxide in solvent, orTFA to provide the compound of formula 110,

oxidizing compound 110 with hydrogen peroxide in the presence ofpotassium bicarbonate and potassium fluoride to provide the compound114;

and debenzylating compound 114 to provide compound
 21. 23. A method forisolating entecavir or an entecavir intermediate from a diluted mixture,the diluted mixture comprising entecavir and water or a mixturecomprising an entecavir intermediate and other process reagentscomprising: (a) adsorbing the diluted mixture onto a hydrophobic resinbed; (b) washing the resin bed with water to remove salt; and (c)eluting the entecavir or entecavir intermediate from the resin bed withan organic solvent.
 24. The method of claim 23 wherein the hydrophobicresin is a brominated styrene based resin.
 25. A process for thepreparation of an ester of the formula

wherein R^(a) is alkyl, phenyl, C₁ to C₆ alkylphenyl, or C₁ to C₆alkoxyphenyl; R^(b) is C₁ to C₆ alkyl; and R is C₁ to C₄ alkyl or benzylcomprising: (a) reacting a cyclopentadienide ion

with a silylating reagent having the formula R^(a)(R^(b))₂Si—Y, whereinY is a leaving group; and (b) reacting the product of step (a) with aketene to give a cyclobutanone of the formula

(c) treating the product from step (b) with a base effective for openingthe cyclobutanone ring; (d) reducing the product from step (c) with areducing agent to give a racemic carboxylic acid of the formula

(e) resolving the product from step (d) by treatment with a chiral amineand separation of the resulting diastereomeric salts to give a compoundof formula

wherein CA represents a chiral amine; and (f) heating the product fromstep (e) in a solution of an acidic solution to give the ester productof formula
 66. 26. The process of claim 25, in which, in step (b), theketene is formed from dichloroacetyl chloride and a base.
 27. Theprocess of claim 25, in which, in step (c), the base is potassiumcarbonate in t-butanol.
 28. The process of claim 25, in which, in step(d), the reducing reagent is NaBH₄.
 29. The process of claim 25, inwhich, in step (e), the chiral amine is selected from the groupconsisting of R,R-(−)-2-amino-1-(4-nitrophenyl)-1,3-propanediol,(1R,2R)-(+)-1,2-diphenylethylenediamine, (R)-(−)-1-cyclohexylethylamine,D-threo-2-amino-1-(4-nitrophenyl)-1,3-propanediol,(1S,2S)-(+)1,2-diaminocyclohexane, dehydroabietylamine,(1R,2R)-1,2-diaminomethylcyclohexane, cichonidine, and cinchonine. 30.The process of claim 25, in which, in step (f), the acidic solutioncomprises a solution of an alcohol, R—OH, wherein R is C₁ to C₄ alkyl orbenzyl, and an acid.
 31. The process of claim 25, in which, in step (b),the ketene is formed from dichloroacetyl chloride and a base; in step(c), the base is potassium carbonate in t-butanol; in step (d), thereducing reagent is NaBH₄; in step (e), the chiral amine isR,R-(−)-2-amino-1-(4-nitrophenyl)-1,3-propanediol; and in step (f), theacidic solution comprises a solution of an alcohol, R—OH, wherein R isC₁ to C₄ alkyl or benzyl, and an acid.
 32. A compound of formula

R^(a) is allyl, phenyl, C₁ to C₆ alkylphenyl or C₁ to C₆ alkoxyphenyl;R^(b) is C₁ to C₆ alkyl; and X^(a) and X^(b) are halide.
 33. A compoundof formula

R^(a) is allyl, phenyl, C₁ to C₆ alkylphenyl or C₁ to C₆ alkoxyphenyl;R^(b) is C₁ to C₆ alkyl; R^(m) is —CO₂R⁶ or —CH₂OR⁶; R⁵ is hydrogen or ahydroxy protecting group; and R⁶ is hydrogen, C₁ to C₄ alkyl, or benzyl.34. A compound of claim 33 wherein: R^(m) is —CO₂R⁶; and R⁵ and R⁶ areboth hydrogen.
 35. The compound of claim 34 wherein: R^(a) is phenyl;and R^(b) is methyl.
 36. A compound of claim 33 as a salt with a chiralamine selected from the group consisting ofR,R-(−)-2-amino-1-(4-nitrophenyl)-1,3-propanediol,(1R,2R)-(+)-1,2-diphenylethylenediamine, (R)-(−)-1-cyclohexylethylamine;D-threo-2-amino-1-(4-nitrophenyl)-1,3-propanediol,(1S,2S)-(+)-1,2-diaminocyclohexane, dehydroabietylamine,(1R,2R)-1,2-diaminomethylcyclohexane, cinchonidine, and cinchonine. 37.The compound of claim 36 wherein: R^(m) is —CO₂R⁶; R⁵ and R⁶ are bothhydrogen; R^(a) is phenyl; R^(b) is methyl; and the chiral amine isR,R-(−)-2-amino-1-(4-nitrophenyl)-1,3-propanediol.
 38. The compound ofclaim 33 wherein: R^(m) is —CH₂OR⁶; R⁵ is hydrogen; and R⁶ is benzyl.39. The compound of claim 38 wherein: R^(a) is phenyl; and R^(b) ismethyl.
 40. A compound having the formula

R^(a) is phenyl; R^(b) is C₁ to C₆ alkyl; R^(m) is —CO₂R⁶ or —CH₂OR⁶; R⁵is hydrogen or a hydroxy protecting group; and R⁶ is hydrogen, C₁ to C₄alkyl, or benzyl, said compound produced according to the process ofclaim
 22. 41. A compound of formula

R^(a) is alkyl, phenyl, C₁ to C₆ alkylphenyl, or C₁ to C₆ alkoxyphenyl;R^(b) is C₁ to C₆ alkyl; and R²⁰ is hydrogen or benzyl.
 42. The compoundof claim 41 wherein: R^(a) is phenyl; R^(b) is methyl; and R²⁰ isbenzyl.
 43. A compound of formula

R^(a) is alkyl, phenyl, C₁ to C₆ alkylphenyl, or C₁ to C₆ alkoxyphenyl;R^(b) is C₁ to C₆ alkyl; R²⁰ is hydrogen or benzyl; X is Cl, I, orbenzyloxy; R^(y) and R^(z) are taken together to form methylene (═CH₂),or R^(y) is OR²³, and R^(z) is —CH₂OR²⁴, wherein R²³ and R²⁴ are eachhydrogen or are taken together to form a ring to define a dioxolane,said dioxolane being optionally substituted with —O(C₁₋₄alkyl) or—O(C═O)(C₄alkyl); and R²⁵ and R²⁶ are both hydrogen, or one of R²⁵ andR²⁶ is hydrogen and the other is acyl; or R²⁵ and R²⁶ are taken togetherto form ═CH(OC₁₋₄alkyl) or ═CH(OC(═O)C₁₋₄alkyl).
 44. The compound ofclaim 43 wherein: R^(a) is phenyl; R^(b) is methyl; and X is benzyloxy.45. The compound of claim 44 in which R²⁰ is benzyl; R^(y) is OH, andR^(z) is —CH₂OH, and R²⁵ and R²⁶ are both hydrogen.
 46. The compound ofclaim 43 wherein: R^(a) is phenyl; R^(b) is methyl; X is benzyloxy;R^(y) is OR²³, and R^(z) is —CH₂OR²⁴, wherein R²³ and R²⁴ combine toform a dioxolane optionally substituted with —O(C₁₋₄alkyl) orO(C═O)(C₁₋₄alkyl); and R²⁵ and R²⁶ are both hydrogen, or R²⁵ and R²⁶ aretaken together to form ═CH(OC₁₋₄alkyl) or ═CH(O(C═O)C₁₋₄alkyl).
 47. Thecompound of claim 43 wherein: R^(a) is phenyl; R^(b) is methyl; X isbenzyloxy; R^(y) and R^(z) are taken together to form methylene; and R²⁵is hydrogen and R²⁶ is acyl.
 48. The compound of claim 43 having theformula,


49. A compound of formula

R^(a) is alkyl, phenyl, C₁ to C₆ alkylphenyl, or C₁ to C₆ alkoxyphenyl;R^(b) is C₁ to C₆ alkyl; and R²⁰ is hydrogen or benzyl.
 50. The compoundof claim 49 wherein: R^(a) is phenyl; R^(b) is methyl; and R²⁰ ishydrogen.
 51. The compound of claim 49 wherein: R^(a) is phenyl; R^(b)is methyl; and R²⁰ is benzyl.
 52. The methanesulfonate salt of thecompound of claim
 51. 53. A compound of formula

X is Cl or I; R^(a) is alkyl, phenyl, C₁ to C₆ alkylphenyl, or C₁ to C₆alkoxyphenyl; R^(b) is C₁ to C₆ alkyl; and R²⁰ is hydrogen or benzyl.54. A compound of formula

wherein R^(b) is C₁ to C₆ alkyl; and R²⁰ is hydrogen or benzyl, or asalt thereof.
 55. The compound of claim 54 wherein R^(b) is methyl. 56.A compound of formula

A is CH₂ or a bond; R²⁷ is hydrogen, benzyl, or SiR^(d) ₂R^(c); R^(c) isC₁ to C₄ alkyl or phenyl; and R^(d) is C₁ to C₃ alkyl.
 57. A compound ofclaim 56, in which A is a bond, and R²⁷ is hydrogen.
 58. A method formaking a compound of formula 78, according to claim 48, comprising, (a)treating an ester of the formula

wherein R^(a) is allyl, phenyl, C₁ to C₆ alkylphenyl, or C₁ to C₆alkoxyphenyl; R^(b) is C₁ to C₆ alkyl; and R is C₁ to C₄ alkyl orbenzyl; with 2-methoxypropene and a catalytic amount of a weak acid toprovide a compound of formula

(b) reducing the carboxylic ester moiety of the compound 74 with atleast one hydride reagent to provide a compound of formula,

(c) protecting the unprotected hydroxy moiety of compound 75, as abenzyl ether upon treatment of compound 75 with a base and a benzylhalide, then removing the MOP group of the compound 75, to provide theallylic alcohol having the formula,

(d) epoxidizing the product from step (c) with a diastereoselectiveexpoxidation, to give a cyclopentane epoxide having the formula

(e) treating the cyclopentane epoxide from step (d) with an alkali metalsalt of a purine compound of formula

wherein X is benzyloxy; I, or Cl, to give a compound of formula
 78. 59.A process for the preparation of entecavir having the formula

(a) converting an ester having the formula

wherein R is C₁ to C₄ alkyl, or benzyl; R^(a) is allyl, phenyl, C₁ to C₆alkylphenyl or C₁ to C₆ alkoxyphenyl, and R^(b) is C₁ to C₆ alkyl, underaminohydroxylation conditions to give an oxazolidinone having theformula

(b) converting the alcohol of the oxazolidinone of formula 67 with aniodide salt to give an iodide having the formula

(c) treating the iodide of formula 68 with zinc and acetic acid; (d)treating the product of step (c) with a hydride reagent to reduce theester moiety to an alcohol and give a methylene compound of formula

(e) reacting the methylene compound of formula 69 with6-chloro-2-amino-5-nitro-4(3H)-pyrimidinone in the presence of base togive a pyrimidine compound having the formula

(f) treating the pyrimidine compound of formula 70 with a reducing agentto reduce the nitro moiety to an amine; (g) cyclizing the product ofstep (f) with an orthoformate derivative and an acid to give a methylenecompound having the formula

(h) converting the silane moiety of the compound of formula 71 to ahydroxy moiety and providing the compound of formula
 21. 60. A processfor the preparation of entecavir having the formula

(a) treating 4-(S)-hydroxy-2-cyclopenten-1-one with a silylating reagentof the formula R^(c)R^(d) ₂SiY and a trialkylamine base wherein R^(c) isC₁ to C₄ alkyl or phenyl, R^(d) is C₁ to C₃ alkyl, and Y is a leavinggroup to give the compound of formula

(b) treating the product from step (a) with a Grignard reagent preparedfrom a (halomethyl)silane reagent of the formula R^(a)R^(b) ₂SiCH₂X′,wherein R^(a) is allyl, phenyl, C₁ to C₆ alkylphenyl or C₁ to C₆alkoxyphenyl; R^(b) is C₁ to C₆ alkyl; and X′ is chloro, bromo, or iodofollowed by treatment with trimethylsilylating reagent to give acompound of formula

(c) formylating the compound of formula 34 to give a compound of formula

(d) treating the compound of formula 35 with a sulfonylating reagenthaving the formula R³SO₂Cl, wherein R³ is C₁ to C₄ alkyl,trifluoromethyl, phenyl or phenyl substituted by C₁ to C₆ alkyl or C₁ toC₆ alkoxy; (e) reacting the product of step (d) with a strong base toeliminate a sulfonate group to provide a methylene compound of formula

(f) selectively reducing the methylene compound of formula 36 with ahydride reagent to provide an allylic alcohol of the formula

(g) condensing the allylic alcohol of the formula 37 under Mitsonobuconditions with a purine compound of formula

wherein X is Cl, I, or benzyloxy, to provide a methylene compound offormula

(h) converting the compound of formula 38 to the compound of formula 21.61. A process for the preparation of entecavir having the formula

(a) reacting a cyclopentenone of the formula

with iodine, wherein R^(c) is C₁ to C₄ alkyl, or phenyl, and R^(d) is C₁to C₃ alkyl; (b) reducing the carbonyl group of the product of step (a)to provide an iodo compound of formula

(c) converting the iodo compound of formula 40 to give a compound offormula

wherein R is C₁ to C₄ alkyl, or benzyl; (d) acylating the compound offormula 41 with an activated acyl agent of the formula R²C(O)—Y whereinR² is C₁ to C₆ alkyl, arylalkyl or aryl, and Y is a leaving group togive a compound of formula

(e) treating the product of step (d) with a Grignard reagent preparedfrom a (halomethyl)silane reagent of the formula R^(a)R^(b) ₂SiCH₂X′,wherein R^(a) is allyl, phenyl, C₁ to C₆ alkylphenyl or C₁ to C₆alkoxyphenyl; R^(b) is C₁ to C₆ alkyl; and X′ is chloro, bromo, or iodoto give an ester of the formula

(f) reducing the ester of formula 43 with a hydride reagent to providean allylic alcohol of the formula

(g) epoxidizing the allylic alcohol of formula 44 with an oxidizingagent to provide a cyclopentane epoxide of the formula

(h) reacting the cyclopentane epoxide of formula 45 with an alkali metalsalt of a purine compound of formula

wherein X is Cl, I or benzyloxy, to give a compound of formula

(i) converting the compound of formula 46 to a methylene compound offormula

(j) treating the compound of formula 47 with an acid or base effectivefor protodesilylation of the silyl moiety; and (k) oxidizing the productof step (O) to provide the compound of formula
 21. 62. A process for thepreparation of entecavir having the formula

(a) treating a homochiral bicyclic lactone of the formula

with paraformaldehyde, acetic acid, and sulfuric acid to provide adiacetate of the formula

(b) treating the diacetate product of step (a) using a base in analcohol solvent to remove the acetate protecting groups to give thecompound having the formula

(c) treating the product of step (b) with a silylating reagent of theformula R^(c)R^(d) ₂SiY, wherein R^(c) is linear or branched C₁ to C₄alkyl, or phenyl, and R^(d) is linear or branched C₁ to C₃ alkyl and Yis a leaving group, to provide a compound of formula

(d) treating the product of step (c) with a strong non-nucleophilic baseand (1S)-(+)-(10-camphorsulfonyl)oxaziridine to give a compound offormula

(e) reducing the lactone moiety of the product from step (d) with ahydride reagent to give a compound having the formula

(f) cleaving the product from step (e) with an oxidizing agent to give acompound of formula

(g) reducing the product from step (f) with a hydride reagent to give adiol of the formula

(h) selectively sulfonylating the primary alcohol of the product fromstep (g) with a reagent of the formula R³SO₂Cl, wherein R³ is C₁ to C₄alkyl, trifluoromethyl, phenyl, or phenyl substituted by C₁ to C₆ alkylor C₁ to C₆ alkoxy; (i) acylating the secondary alcohol of the productof step (h) with an acylating agent of the formula R²C(O)—Y, wherein R²is C₁ to C₆ alkyl, arylalkyl or aryl, and Y is a leaving group to give acompound having the formula

(j) treating the product from step (i) with a strong base to effectelimination and hydrolysis of the carboxylic acid ester to give thecompound of formula

(k) condensing the product from step (J) with a purine compound offormula

wherein X is Cl, I or benzyloxy, under Mitsonobu conditions to give amethylene compound of formula

(l) removing the silyl ether protecting groups of the methylene compoundof formula 57; and (m) hydrolyzing the 6-X group to give the compound offormula
 21. 63. A process for the preparation of entecavir having theformula

(a) reducing the compound of formula

to give a lactol of the formula

wherein R^(c) is a linear or branched C₁ to C₄ alkyl, or phenyl, andR^(d) is a linear or branched C₁ to C₃ alkyl; (b) iodinating the lactolproduct of step (a) by free radical oxidation to give an iodide compoundhaving the formula

(c) treating the product from step (b) with a strong base to give themethylene compound of formula

(d) condensing the product from step (c) with a purine compound offormula

wherein X is Cl, I or benzyloxy, under Mitsonobu conditions to give amethylene compound of formula

(e) removing the silyl ether protecting groups of the methylene compoundof formula 57; and (f) hydrolyzing the 6-X group to give the compound offormula
 21. 64. A process for the preparation of entecavir having theformula

(a) silylating a compound of formula

with a compound of formula R^(c)R^(d) ₂SiY, wherein R^(c) is linear orbranched C₁ to C₄ alkyl, or phenyl, R^(d) is linear or branched C₁ to C₃alkyl, and Y is a leaving group, to provide a compound of formula

(b) reducing the product from step (a) under conditions sufficient toremove the benzyl protecting group to give a compound of formula

(c) converting the alcohol moiety of the product from step (b) to asulfonate ester of the formula SO₂R³, wherein R³ is C₁ to C₄ alkyl,trifluoromethyl, or phenyl substituted by C₁ to C₆ alkyl or C₁ to C₆alkoxy to give a compound of formula

(d) treating the product from step (c) with a strong base to effectelimination of the R³SO₃H to provide the methylene compound of formula

(e) treating the product from step (d) with a lithium salt of1,3-dithiane to provide the compound of formula

(f) hydrolyzing the dithioacetal moiety of the compound of formula 87;and (g) treating the product of step (f) with a hydride reagent toprovide a compound of formula

(h) acylating the compound of formula 88 with a compound having theformula R²C(O)—Y, wherein Y is a leaving group and R² is C₁ to C₆ alkylor aryl, to give the compound of formula

(i) condensing the product from step (h) with a purine compound offormula

wherein X is Cl, I, or benzyloxy under Mitsonobu conditions to give amethylene compound of formula

(j) removing the acyl ester protecting groups from the methylenecompound of formula 90; and (k) hydrolyzing the X group to give thecompound of formula
 21. 65. A process of preparing entecavir having theformula

(a) reducing an ester of the formula

wherein R is C₁ to C₄ alkyl, or benzyl, and R′ is benzyl, benzylsubstituted on the phenyl moiety by C₁ to C₆ alkyl or C₁ to C₆ alkoxy,or R^(c)R^(d) ₂Si wherein R^(c) is linear or branched C₁ to C₄ alkyl orphenyl, and R^(d) is linear or branched C₁ to C₃ alkyl, with a hydridereagent; (b) asymmetrically epoxidizing the product from step (a) with ahomochiral diester of tartaric acid, a hydroperoxide, and a metalcatalyst to provide the cyclopentane epoxide of the formula

(c) treating the product of step (b) with an alkali metal salt of apurine compound of formula

wherein X is Cl, I or BnO, to provide a compound of formula

(d) converting the vicinal diol product of step (c) to an alkene toprovide the methylene compound of formula

(e) hydrolyzing the X group of the compound of formula 19 to provide themethylene compound of formula

(f) removing the benzyl ether protecting group(s) to provide thecompound of formula
 21. 66. A process for the preparation of an ester ofthe formula

wherein R is C₁ to C₄ alkyl or benzyl, comprising: (a) acetylating adiol of the formula

with an anhydride to provide the diacetate of the formula

(b) hydrolyzing the product from step (c) with a hydrolase enzyme togive a compound of formula

(c) coupling the product from step (b) with phenylsulfonylnitromethaneto give a compound of formula

(d) alkylating the product from step (c) with a benzyl halide to providethe compound of formula

(e) converting the product from step (d) to an ester of the formula

(f) isomerizing the ester of the formula 6 under basic conditions toprovide the ester of the formula
 7. 67. A process for the preparation ofan ester of the formula

wherein R is C₁ to C₄ alkyl or benzyl, comprising: (a) asymmetricallyacetylating the diol of the formula

with a C₁ to C₆ alkyl acetate ester and hydrolase enzyme to obtain acompound of formula

(b) acylating the product from step (a) to give an alkyl carbonate ofthe formula

wherein R⁴ is C₁ to C₆ alkyl, benzyl, phenyl, or phenyl substituted byC₁ to C₆ alkyl or C₁ to C₆ alkoxy; (c) coupling the product from step(b) with phenylsulfonylnitromethane to obtain a compound of formula

(d) hydrolyzing the product from step (c) with a base to obtain acompound of formula

(e) alkylating the product from step (d) with a benzyl halide in thepresence of strong non-nucleophilic base to give the compound of formula

(f) converting the product from step (e) to an ester of the formula

(g) isomerizing the ester of the formula 6 under basic conditions toprovide the ester of the formula
 7. 68. A process for the preparation ofan ester of the formula

wherein R is C₁ to C₄ alkyl or benzyl, comprising: (a) reacting acyclopentane epoxide of the formula

with a strong non-nucleophilic base to form an allylic alcohol of theformula

(b) acylating the product from step (a) to give an alkyl carbonate esterof the formula

wherein R⁴ is C₁ to C₆ alkyl, benzyl, phenyl, or phenyl substituted byC₁ to C₆ alkyl or C₁ to C₆ alkoxy; (c) coupling the product of step (b)with phenylsulfonylnitromethane to give the compound of formula

(d) converting the product from step (c) to an acid of the formula

(e) converting the product from step (d) to an ester of the formula

(f) isomerizing the product from step (e) under basic conditions toprovide the ester of formula
 7. 69. A process of preparing an ester ofthe formula

wherein R is C₁ to C₄ alkyl, or benzyl; R′ is benzyl, or benzylsubstituted on the phenyl moiety by C₁ to C₆ alkyl or C₁ to C₆ alkoxy,or R^(c)R^(d) ₂Si, wherein R^(c) is C₁ to C₄ alkyl, or phenyl, and R^(d)is C₁ to C₃ alkyl; comprising: (a) oxidizing an allylic alcohol of theformula

with an oxidizing agent to give a cyclopentenone of the formula

(b) reducing the cyclopentenone of the formula 80 with lithiumtri-sec-butylborohydride; (c) sulfonylating the product of step (b) witha triflating reagent to give a compound of formula

(d) converting the triflate moiety of the compound of formula 81 to analkoxycarbonyl moiety to give the ester of the formula
 7. 70. A compoundof formula

wherein R^(a) is allyl, phenyl, C₁ to C₆ alkylphenyl or C₁ to C₆alkoxyphenyl; and R^(b) is C₁ to C₆ alkyl; or a salt thereof.
 71. Acompound of formula

or a salt thereof wherein R¹ is benzyl or R^(c)R^(d) ₂Si—, R^(c) is C₁to C₄ alkyl or phenyl, and R^(d) is C₁ to C₃ alkyl.
 72. A compound offormula

R^(a) is allyl, phenyl, C₁ to C₆ alkylphenyl or C₁ to C₆ alkoxyphenyl;R^(b) is C₁ to C₆ alkyl; R^(c) is C₁ to C₄ alkyl or phenyl; and R^(d) isC₁ to C₃ alkyl.
 73. A compound of formula

R^(a) is allyl, phenyl, C₁ to C₆ alkylphenyl or C₁ to C₆ alkoxyphenyl;R^(b) is C to C₆ alkyl; R^(c) is C₁ to C₄ alkyl or phenyl; and R^(d) isC₁ to C₃ alkyl.
 74. A compound of formula

wherein Z₁ and Z₂ are both R^(c)R^(d) ₂SiO— and Z₃ is hydroxy or Z₁ andZ₂ are both hydroxy and Z₃ is R^(c)R^(d) ₂SiO—; R^(c) is C₁ to C₄ alkylor phenyl; and R^(d) is C₁ to C₃ alkyl.